Clin Pharmacokinet 2004; 43 (8): 487-514

REVIEW ARTICLE 0312-5963/04/0008-0487/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Drug Transfer and Metabolism by the

Human Placenta
Michael R. Syme, James W. Paxton and Jeffrey A. Keelan
Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences,
University of Auckland, Auckland, New Zealand

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
1. Placental Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
2. Drug Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
2.1 Passive Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
2.1.1 Drug Properties Affecting Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
2.1.2 Maternal, Placental and Fetal Characteristics Affecting Drug Transfer . . . . . . . . . . . . . . . 494
2.2 Facilitated Diffusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
2.3 Active Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
2.3.1 P-Glycoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
2.3.2 Multidrug Resistance Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
2.3.3 Breast Cancer Resistant Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
2.3.4 Monoamine Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
2.3.5 Novel Organic Cation Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
2.3.6 Monocarboxylate Transporters and the Dicarboxylate Transporter . . . . . . . . . . . . . . . . . . 498
2.3.7 Sodium/Multivitamin Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
3. Drug Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
3.1 Phase I Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
3.1.1 Cytochrome P450 (CYP) 1 Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
3.1.2 CYP2 Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.1.3 CYP3 Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.2 Phase II Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.2.1 Uridine Diphosphate Glucuronosyltransferases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.2.2 Glutathione S-Transferases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
3.2.3 Epoxide Hydrolase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
3.2.4 Sulfotransferases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
4. Models to Study Drug Transfer and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
4.1 In Vitro Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
4.1.1 Perfused Placental Cotyledon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
4.1.2 Tissue Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
4.2 In Vivo Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
5. Clinical Significance of Placental Transfer and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
6. Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
488 Syme et al.

Abstract The major function of the placenta is to transfer nutrients and oxygen from the
mother to the foetus and to assist in the removal of waste products from the foetus
to the mother. In addition, it plays an important role in the synthesis of hormones,
peptides and steroids that are vital for a successful pregnancy. The placenta
provides a link between the circulations of two distinct individuals but also acts as
a barrier to protect the foetus from xenobiotics in the maternal blood.
However, the impression that the placenta forms an impenetrable obstacle
against most drugs is now widely regarded as false. It has been shown that that
nearly all drugs that are administered during pregnancy will enter, to some degree,
the circulation of the foetus via passive diffusion. In addition, some drugs are
pumped across the placenta by various active transporters located on both the fetal
and maternal side of the trophoblast layer. It is only in recent years that the impact
of active transporters such as P-glycoprotein on the disposition of drugs has been
demonstrated. Facilitated diffusion appears to be a minor transfer mechanism for
some drugs, and pinocytosis and phagocytosis are considered too slow to have any
significant effect on fetal drug concentrations.
The extent to which drugs cross the placenta is also modulated by the actions of
placental phase I and II drug-metabolising enzymes, which are present at levels
that fluctuate throughout gestation. Cytochrome P450 (CYP) enzymes in particu-
lar have been well characterised in the placenta at the level of mRNA, protein, and
enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been detected in
the term placenta. While much less is known about phase II enzymes in the
placenta, some enzymes, in particular uridine diphosphate glucuronosyltransfer-
ases, have been detected and shown to have specific activity towards marker
substrates, suggesting a significant role of this enzyme in placental drug detoxifi-
cation.
The increasing experimental data on placental drug transfer has enabled
clinicians to make better informed decisions about which drugs significantly cross
the placenta and develop dosage regimens that minimise fetal exposure to poten-
tially toxic concentrations. Indeed, the foetus has now become the object of
intended drug treatment. Extensive research on the placental transfer of drugs
such as digoxin and zidovudine has assisted with the safe treatment of the foetus
with these drugs in utero. Improved knowledge regarding transplacental drug
transfer and metabolism will result in further expansion of pharmacological
treatment of fetal conditions.

The placenta separates the blood supply of two
human beings, mother and foetus, while being si-
multaneously perfused by both their circulations. It
acts to supply the foetus with oxygen and nutrients
from the mother and also functions as an active
endocrine organ vital to successful pregnancy. This
makes the placenta a unique organ system in the
body. Nutrients such as glucose, amino acids and
vitamins are transferred across the placenta via spe-
cific transport mechanisms present in the
maternal-facing apical (brush border) membrane
and fetal-facing basal membrane of the syncytio-
trophoblast.[1-3] At the same time, metabolic waste
products are cleared from fetal blood across the
placenta into the maternal circulation, again using
specific transport mechanisms in many cases.[4]
For some compounds, the placenta offers a pro-
tective barrier for the developing foetus by reducing

© 2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism 489

Gestational
Maternal drug Mother membranes
administration Amniotic
fluid

Bound drug Bound

Fetus
drug

Placenta Free drug

Site of action Umbilical
Passive arteries
diffusion Liver
Site of action

Metabolites Free drug Active

Metabolites
transport
Gut

Metabolism Swallowing
Metabolism

Liver Umbilical
vein

Kidney

Kidney Fetal urine

Meconium

Excretion

Fig. 1. Drug disposition in mother and foetus after maternal drug administration. A variety of pharmacokinetic variables, including
transplacental transport and metabolism, determine the degree of maternal-to-fetal drug transfer and fetal drug exposure. Black arrows
represent parent drug and white arrows represent metabolites. The size of the arrows approximates relative importance, although this is
drug-dependent and will vary during pregnancy with fetal and placental maturation.

the entry of various xenobiotics from the mother to
the foetus, while for others it facilitates their passage
both to and from the fetal compartment (figure 1).
Hence, the placenta can act much the same as the
kidney or liver in the elimination of xenobiotics.
Since placental transfer of drugs from the maternal
to the fetal side occurs primarily via passive diffu-
sion, the physicochemical properties of drugs such
as lipid solubility, polarity and molecular weight
primarily determine the rate of transfer across the
placenta. According to membrane permeability
properties, low-molecular-weight, lipid-soluble and
un-ionised compounds can easily cross membranes,
such as the human placenta. The degree of binding
to plasma proteins may also affect the amount trans-
ferred.[5]
The transfer of foreign chemicals across the pla-
centa can also be modified by metabolism in the
placenta itself. The human placenta contains multi-
ple enzyme systems, including those responsible for
drug oxidation, reduction, hydrolysis and conjuga-
tion.[6-9] However, the activities of these enzymes
are usually relatively minor compared with those of
the maternal or fetal liver and these systems are
thought to be primarily involved with endogenous
steroid metabolism.[10]
Drug administration to pregnant women must
always be cognisant of the potential for fetal expo-
sure; where possible this should be minimised, for

© 2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (8)
490
example through selection of pharmaceuticals with
poor placental transfer. On the other hand, when
drugs are administered to the mother for the pharma-
cological benefit of the foetus, it is necessary that
these drugs reach therapeutic concentrations in the
fetal circulation. In both of these scenarios the im-
pact of placental metabolism and uptake remains
difficult to quantify.
This review discusses the current understanding
of drug transfer and metabolism in the human pla-
centa and its clinical implications.
1. Placental Anatomy and Physiology
Mammalian placentas can be classified into three
general types according to the number of layers
between maternal and fetal blood: (i) haemochorial
(rat, rabbit, guinea pig); (ii) endotheliochorial (cat,
dog); and (iii) epitheliochorial (sheep, pig, horse).[11]
The structural differences in placentas from differ-
ent species affects their function. In particular, the
transfer and metabolism of drugs varies enormously
between species, making data from animal studies
difficult to interpret with respect to predicting feto-
maternal drug disposition in human pregnancy.[11]
The human placenta is of the haemochorial type, in
which the fetal tissue is in direct contact with the
maternal blood (figure 2).[12] It is composed
primarily of fetal villus tissue, covered at the mater-
nal face with decidual membrane which lines the
pregnant uterus. The layer of tissue separating
maternal and fetal circulations consists of the endo-
thelium of the fetal capillaries and the trophoblast,
containing the villus stroma, the cytotrophoblast and
the syncytiotrophoblast.[11] In early pregnancy, this
tissue layer is about 50–100μm in thickness, which
decreases to 4–5μm in late gestation as the placenta
grows and matures.[12] This thinning is mainly due to
the partial disappearance of the cytotrophoblastic
layer.[11] The placenta contains organelles which are
essential for biochemical synthesis and exchange,
such as mitochondria, ribosomes, pinocytotic vacu-
oles and lipid enclosures.
The human placenta is composed of 20–40 com-
partments called cotyledons, each functioning as a
vascular unit within the placenta.[11,14] Every
© 2004 Adis Data Information BV. All rights reserved.
Syme et al.
cotyledon contains a villus tree formed on the fetal
side of term placenta (figure 3). The villus tree
consists of a central fetal capillary, villus stroma and
an outer trophoblast layer that is bathed in maternal
blood. This outer layer is comprised of a multinucle-
ated syncytiotrophoblast membrane formed by fu-
sion of mononuclear cytotrophoblastic stem cells.
Each trunk and its branches float in a space limited
on the maternal side by the basal plate, on the fetal
side by the chorionic plate and laterally by decidual
septa. Some branches of the villus trunk are attached
to the basal plate and are called anchoring villi.
In the first 2 months of pregnancy, the major
organs of the human embryo develop (organogene-
sis) and its shape becomes clearly defined. At the
end of the second month, the embryo becomes a
foetus. During the following 7 months, the foetus
increases in size and weight and its organs undergo
maturation at the histological and functional levels.
Maternal blood does not perfuse the placenta during
the embryonic period and the feto-placental-mater-
nal circulation does not become established until
around the tenth week of pregnancy. Hence, drugs
and other chemicals that are present in the maternal
blood during the first 10 weeks of gestation must be
delivered to the developing embryo via diffusion
through extracellular fluid in order to interfere with
morphological differentiation. Chemical or drug-
induced dysmorphogenicity has been recognised in
animals for decades.[15-17] However, the clinical im-
plications of these experimental results were dra-
matically demonstrated in 1961 with the pandemic
of thalidomide-induced phocomelia and other em-
bryopathies.[18]
2. Drug Transfer
Transplacental exchanges are known to involve
passive transfer, active transport, facilitated diffu-
sion, phagocytosis and pinocytosis.[19] Only the pas-
sive transfer of drugs across the placenta has re-
ceived much attention by investigators, although
active transport systems are being identified for an
increasing number of drugs. It appears that phagocy-
tosis and pinocytosis are too slow to have any signif-
icant influence on the extent of transfer of drugs.
Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism 491

Decidua parietalis
Umbilical vein Umbilical arteries
(O2-rich blood) (O2-poor blood) Smooth chorion
Amniochorionic membrane
Fetal circulation Intervillous space Amnion
Chorionic plate
Stump of
Main stem villus main stem villus

Placental septum

Anchoring villus
Decidua basalis
Cytotrophoblastic shell
Myometrium
Endometrial Endometrial
veins arteries

Maternal circulation
Fig. 2. Schematic drawing of a transverse section through a full-term human placenta. The villus branches are bathed in maternal blood and
provide a large surface area for transplacental exchange. Oxygen-deficient fetal blood is pumped through two umbilical arteries and into the
villus trees where exchange of gases, nutrients, waste products and xenobiotics takes place. The oxygen-rich blood re-enters the fetal
compartment through the umbilical vein (from Moore and Persaud,[13] with permission).

2.1 Passive Transfer
Passive transfer is the predominant form of ex-
change in the placenta and represents the permeation
of a molecule down its concentration gradient. Pas-
sive diffusion does not require the input of energy, is
not saturable and is not subject to competitive inhi-
bition. When drugs cross the placenta by passive
diffusion, the amount that crosses in any given time
is dependent on the concentration of the drug in the
maternal circulation, its physicochemical properties
and the properties of the placenta that determine
how readily the drug will pass. The eventual result is
for concentrations on either side of the placenta to
equalise (unless the rate of transfer is too slow for
equilibrium to be reached). The maternal plasma
concentration at steady-state conditions (Css) is de-
pendent on the overall maternal clearance and the
rate of drug entry into the body (equation 1):
Rate in
Css =
CL
(Eq. 1)
where ‘Rate in’ = rate of maternal drug adminis-
tration and CL = maternal clearance.

© 2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (8)
492 Syme et al.

Endothelium of
fetal capillary

Placental Connective tissue

Arteriocapillary core of villus
venous network membrane

Fetal capillaries

Hofbauer
Branch villus cells b
Cytotrophoblast
Syncytiotrophoblast

Nuclear aggregation
Persisting or syncytial knot
cytotrophoblast cells
Syncytiotrophoblast

Fibrinoid Oxygen-rich
material fetal blood

Oxygen-poor
Chorionic plate
blood in fetal
Vein capillary
Amnion
Arteries Placental
membrane
a c
Fig. 3. (a) Structure of the placental villus tree. Fetal blood flows into the villus stem arteries from the chorionic plate arteries and then into
the arteriocapillaries in the villus branches where the main exchange of material between the mother and foetus occurs. (b) and (c),
drawings of cross-sections through a villus branch at 10 weeks and full term, respectively. The placental membrane (barrier) consists of the
syncytiotrophoblast, cytotrophoblast and fetal capillary endothelium. This membrane decreases in thickness throughout gestation due to
thinning of the syncytiotrophoblast and the break-up of the cytotrophoblastic layer. Hofbauer cells are believed to be phagocytic cells (from
Moore and Persaud,[13] with permission).

The overall maternal plasma clearance will
largely depend on the intrinsic ability of the liver to
metabolise the drug or the kidney to excrete it, or a
combination of both, depending on the physico-
chemical properties of the drug. A modified form of
the Henderson-Hasselbach equation can be used to
calculate the fetal/maternal free drug concentration
ratio by correcting for differences between the un-
bound fractions, the degree of ionisation and the
clearances from the mother and foetus (equation
2):[20]
F/ M =
% unbound M 1 + 10pKa − pH F CL MF
× pKa − pH
× lipid bilayer membrane, so only the non-protein-
% unbound F 1 + 10 M CL FM + CL F
(Eq. 2)
where % unboundM = percentage of drug un-
bound in the maternal circulation, % unboundF =
percentage of drug unbound in the fetal circulation,
pHF = pH of the fetal circulation, pHM = pH of the
maternal circulation, CLMF = clearance from the
maternal circulation into the fetal circulation, CLFM
= clearance from the fetal circulation into the mater-
nal circulation and CLF = clearance from the fetal
circulation.
2.1.1 Drug Properties Affecting Transfer
Passive diffusion is favoured for low-molecular-
weight and highly lipid-soluble drugs that are pre-
dominantly un-ionised.[21] The placenta resembles a
bound portion of a drug is free to diffuse across it,
although substances that transfer by a mechanism

© 2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism
other than passive diffusion may not necessarily
follow these principles.[5]
Drugs with a molecular weight >500Da often
have incomplete transfer across the placenta.[22]
Drugs with a molecular weight >1000Da cross
very poorly. For example, various heparins (mo-
lecular weight range 3000–15 000Da) do not trans-
fer across the placenta because of their relatively
high molecular weight.[23-26] Since most drugs have
a molecular weight <500Da, size rarely limits the
rate of drug transfer through the placenta. Lipid
solubility is also an important factor determining the
transfer of a drug across a biological membrane.
Drugs that are lipid-soluble will pass easily
through the placenta, whereas more hydrophilic
drugs are generally impeded. The partition co-
efficient between octanol and a pH 7.4 aqueous
buffer is a useful measure of lipophilicity and is
often used to predict the transfer of drugs across the
placenta.[27]
Most drugs are weak acids or bases and thus
dissociate at physiological pH. In its ionised form, a
drug is charged and typically cannot pass through
the lipid membrane of the placenta. Differences
between the fetal and maternal pH influence the
fetal/maternal concentration ratio for free drug, but
do not change the un-ionised concentrations. Fetal
pH is lower than maternal pH, so fetal concentra-
tions of bases should exceed those in the maternal
circulation at equilibrium.[21] Under normal condi-
tions, fetal pH is only about 0.1 pH units below that
of the mother and the pH differential can be disre-
garded. However, fetal pH may fall considerably
lower in cases of fetal compromise, resulting in
decreased transfer of basic drugs from the fetal to
the maternal compartment. For example, fetal con-
centrations of lidocaine increase during labour and
delivery and can lead to greater negative effects in
the foetus or neonate.[20]
The complex formed when drugs bind to plasma
proteins is too large to cross the placenta. However,
binding is a transitory phenomenon, so when the
drug separates from the protein, it can cross the
placenta before it binds to another protein binding
site. Usually the unbound drug eventually establish-
© 2004 Adis Data Information BV. All rights reserved.
493
es an equilibrium across the placenta between the
maternal and fetal circulations, unless the rate of
transfer across the placenta is so slow that it never
reaches equilibrium.[5] Although plasma protein
binding alters the total concentration of drugs in the
maternal and fetal plasma, the free concentrations in
the mother and foetus will not differ.[5] Only un-
bound drug is pharmacologically active; neverthe-
less, understanding drug binding is important in the
interpretation of the fetal/maternal total drug con-
centration ratio at steady state.
Although a number of different plasma proteins
have been implicated in drug binding, only albumin
and α1-acid glycoprotein have been shown to bind a
wide variety of drugs. Generally, albumin is seen as
the binding protein for acidic lipophilic drugs and
α1-acid glycoprotein for basic lipophilic drugs.[28,29]
Maternal α1-acid glycoprotein concentrations re-
main relatively constant throughout gestation,
whereas fetal levels increase from about 10% of the
maternal level at 12 weeks to 30–40% at term.[30]
This means that the free fraction of basic drugs, such
as bupivacaine and alprenolol, is elevated in the
foetus.[31,32] In contrast, there is a striking reduction
in the maternal albumin concentration during gesta-
tion, although fetal serum albumin concentrations
increase with gestational age.[33,34] Thus, there is a
gradual rise in the fetal-maternal serum albumin
concentration ratio from about 30% at 12 weeks to
about 120% at term.[33,34] Moreover, some disease
processes and therapeutic procedures reduce mater-
nal protein binding (e.g. preeclampsia, aggressive
fluid hydration prior to regional anaesthesia) and
may increase drug transfer to the foetus.[5,35] Predict-
ing how the placental transfer of any particular drug
will be influenced by changes in fetal or maternal
plasma protein concentrations is often difficult. For
example, digoxin is only 25% bound to plasma
proteins in maternal plasma but its placental transfer
is greatly dependent on the albumin concentration
during in vitro placental perfusion experiments.[36,37]
Factors other than differing plasma protein con-
centration in the fetal and maternal circulations may
also affect the fetal/maternal total drug concentra-
tion ratio. Fetal and maternal forms of albumin have
Clin Pharmacokinet 2004; 43 (8)
494
been shown to have a different structure, with mater-
nal albumin exhibiting higher affinity for some
drugs, such as local anaesthetics, phenobarbital and
phenytoin, whereas for other drugs such as salicy-
lates it is lower.[38-40] Also, binding to plasma pro-
teins is a competitive process between drugs and
endogenous ligands, especially free fatty acids.[41,42]
The concentration of free fatty acids at term is
approximately three times higher in maternal com-
pared with fetal plasma.[41,42] The greater maternal
concentration may result in a higher than expected
fetal/maternal plasma concentration ratio for some
drugs such as diazepam.[41,42] However, differences
between fetal and maternal protein binding are
mostly due to the different concentrations of these
proteins in maternal and fetal plasma, rather than
varying protein structures or competing endogenous
ligands.[5]
A number of drugs have also been found to bind
to placental tissue, which accumulates the drugs by
acting as a depot. How this ‘depot phenomenon’
observed in vitro can be extrapolated to the in vivo
situation is unclear. The transfer of any lipophilic
drug across the placenta first involves the uptake of
the drug into the syncytiotrophoblast.[43] If the affin-
ity for the tissue is high, the drug will not readily be
released into the fetal circulation.[44] Thus, high
lipophilicity does not necessarily translate into high
placental drug transfer. Using the in vitro placental
perfusion model, Nanovskaya et al.[45] found that
buprenorphine was sequestered into the placenta,
reducing its maternal and fetal concentrations.
During the subsequent 2-hour washout period, the
tissue-bound buprenorphine was released slowly
into both circulations. Ala-Kokko et al.[46] showed
that although bupivacaine transferred from the
maternal side more rapidly than lidocaine due to its
higher lipophilicity, less drug appeared in the fetal
circulation due to placental sequestration.
Ala-Kokko and colleagues[44] have suggested that
the distribution of a compound in the maternal-
placental-fetal unit is determined primarily by the
relative affinities of the drug for the maternal and
fetal plasma proteins and the placental tissue. This
means that the extent to which plasma protein bind-
© 2004 Adis Data Information BV. All rights reserved.
Syme et al.
ing affects transfer is probably dependent on the
affinity of the drug for both tissue and plasma pro-
teins. For example, by increasing the circulating
fetal albumin concentration in an in vitro perfusion
system, Dancis et al.[47] showed that there was an
increase in the fetal steroid concentration resulting
from more drug being released from the tissue to the
fetal side.
2.1.2 Maternal, Placental and Fetal Characteristics
Affecting Drug Transfer
Distribution from the maternal circulation into
the placenta is the first step for a drug to transfer
across the placenta and is primarily a function of the
uterine blood flow and the permeability of the pla-
cental membrane. Placental transfer for a particular
drug can generally be referred to as either permea-
bility-limited (hydrophilic drugs), flow-limited (li-
pophilic drugs), or both. The rate of passage of a
drug across a membrane by passive diffusion is
directly linked to the surface area available for
exchange (3.4–12.6m2), membrane thickness
(4–100μm) and blood flow perfusing the membrane
(50–600 mL/min).[12,48] The large range in these
parameters is due to changes in placental structure
throughout pregnancy.[12] Passive diffusion can be
described by Fick’s Law (equation 3):
D × S × (CM − CF )
Vdiff =
a
(Eq. 3)
where Vdiff = rate of diffusion, D = diffusion
coefficient, S = surface area of exchange, CM =
concentration in the maternal circulation, CF = con-
centration in the fetal circulation and a = thickness
of the placenta.
The placenta undergoes considerable change
throughout gestation as part of the normal matura-
tion process, and sometimes as a result of disease.[49]
The combination of increasing placental surface
area and placental thinning during gestation keeps
up with the increasing nutritional and energy re-
quirements of the foetus. The average exchange area
(i.e. the villus surface) ranges from 3.4 m2 at 28
weeks gestation to 12.6 m2 at term.[48-50] The diffu-
sion distance across the placenta decreases from
Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism
50–100 μm at the second month to 4–5 μm at
term.[12]
Most drug molecules are small and relatively
lipid-soluble. Therefore, the limiting factor in their
rate of placental transfer is placental blood flow.[51]
At term, blood enters the spaces between the villi
from over 100 spiral arteries; over 150mL of blood
may be contained in these spaces at a given time.
The rate of blood flow increases during gestation
from about 50 mL/min at 10 weeks to 600 mL/min
at term.[12] Changes in blood flow will not affect
mean steady-state concentrations but under non-
steady-state conditions may accelerate or delay
transfer. The intermittent decreases in placental
blood flow during labour and delivery may not only
delay the transfer of drugs to the foetus, but may
also delay the clearance of drugs already in the
foetus. Even in pregnant women who are only
slightly hypertensive, there are notable changes in
local blood-flow patterns that may affect the placen-
tal transfer of many substances.[52]
In foetuses with severe cardiac insufficiency,
there may be an elevated umbilical venous pressure
that may lead to placental oedema. Clinical observa-
tions suggest that placental transfer of various drugs
may be reduced in patients with an elevated umbili-
cal venous pressure and therapy may therefore be-
come ineffective.[53] A recent study demonstrated
that elevated umbilical venous pressure simulated in
perfused human placentas in vitro reduced the influx
of digoxin and flecainamide into the fetal compart-
ment.[54]
2.2 Facilitated Diffusion
Facilitated diffusion requires the presence of a
carrier substance within the placenta and the system
can become saturated at high concentrations relative
to the Michaelis-Menten constant (Km). However,
transport by this mechanism does not require any
input of energy. Usually, the end result of this mech-
anism of transport is that the concentration in both
the maternal and fetal circulations is equal. It may be
that for many substances, such as carbohydrates,
facilitated diffusion provides a means to increase
transport rates when the functional and metabolic
© 2004 Adis Data Information BV. All rights reserved.
495
needs of the foetus would not be met by passive
diffusion alone.[55] So far only a few drugs have
been suggested to be transported across the placental
barrier by facilitated diffusion. Ganciclovir has been
demonstrated to be taken up into maternal-facing
syncytiotrophoblast vesicles by a carrier-dependent
system.[56] However, overall transfer across the per-
fused placental cotyledon from the maternal-to-fetal
circulations was a passive process. This suggests the
rate-limiting transfer mechanism for ganciclovir is
passive diffusion and facilitated diffusion is only
involved in the initial uptake into the syncytio-
trophoblast. Placental carrier-mediated transport
systems have also been found in maternal-facing
syncytiotrophoblast membrane vesicles for the
cephalosporin cephalexin and glucocorticoids.[57,58]
It seems likely that the facilitated diffusion of drugs
into the syncytiotrophoblast from the maternal side
is actually intended for structurally related endoge-
nous compounds, such as hormones and nucleo-
sides.
2.3 Active Transport
Active transport across the placental membrane
by protein ‘pumps’ requires energy, usually by
adenosine triphosphate (ATP) hydrolysis or energy
stored in the transmembrane electrochemical gradi-
ent provided by Na+, Cl– or H+. Transporters pow-
ered by electrochemical gradients are often classi-
fied as secondary active co-transporters. All active
transporters may work against a concentration gra-
dient but can become saturated.[4] Many investiga-
tors have examined the placental transport systems
of nutrients such as amino acids, vitamins and glu-
cose, but little is known about the active transport of
drugs across the placental barrier.[2,3,59] Drugs that
are actively transported are often structurally similar
to endogenous substrates. Active drug transporters
are located either in the maternal-facing brush-bor-
der (apical) membrane or the fetal-facing basolateral
(basal) membrane where they pump drugs into or
out of the syncytiotrophoblast (table I). This section
will deal with active transporters identified in the
placenta which have demonstrated functional ac-
tivity towards various drugs. Readers are directed to
Clin Pharmacokinet 2004; 43 (8)
496 Syme et al.

Table I. Localisation and function of placental drug transporters involved in drug transfer
Active transporter
P-glycoprotein (PGP)
Multidrug resistance protein 1
(MRP1)
Multidrug resistance protein 2
(MRP2)
Multidrug resistance protein 3
(MRP3)
Breast cancer resistant protein
(BCRP)
Serotonin transporter (SERT)
Norepinephrine transporter
(NET)
Extraneuronal monoamine
transporter (OCT3)
Novel organic cation
transporters (OCTN)
Monocarboxylate transporters
(MCT)
Dicarboxylate transporters
(NaDC3)
Sodium/multivitamin transporter Maternal-to-fetal transfer of
(SMVT)
a Not all have been examined in the human placenta.
Physiological function in placenta
Fetal-to-maternal transfer of
hydrophobic cationic
compounds
Fetal-to-maternal transfer of
glutathione, sulfate and
glucuronide conjugates
(dianonic sulfated bile salts)
Fetal-to-maternal transfer of
glutathione, sulfate, and
glucuronide conjugates
(dianionic sulfated bile salts,
bilirubin glucuronide,
estradiol glucuronide)
Fetal-to-maternal transfer of
anionic conjugates
Unknown
Serotonin transfer
Dopamine and norepinephrine
transfer
Serotonin, dopamine,
norepinephrine, histamine
transfer
Maternal-to-fetal transfer of
carnitine
Fetal-to-maternal transfer of
lactate and pyruvate
Maternal-to-fetal transfer of
succinate and α-ketoglutarate
biotin and pantothenate
Location in placenta
Apical syncytiotrophoblast
Capillary endothelial cells,
apical syncytiotrophoblast
Apical syncytiotrophoblast
Capillary endothelial cells
and apical
syncytiotrophoblast
Probably apical membrane
Apical syncytiotrophoblast
Apical syncytiotrophoblast
Probably basal
syncytiotrophoblast
Basal syncytiotrophoblast
Apical syncytiotrophoblast,
and possibly basal
syncytiotrophoblast
Apical syncytiotrophoblast
Apical syncytiotrophoblast
Substratesa
Digoxin, ciclosporin, saquinavir,
vincristine, vinblastine, paclitaxel,
dexamethasone, sirolimus,
quinidine, terfenadine,
ondansetron, loperamide
Methotrexate, etoposide,
vincristine, vinblastine, cisplatin,
HIV protease inhibitors
Etoposide, cisplatin, doxorubicin,
vincristine, vinblastine,
methotrexate, paracetamol
glucuronide, grepafloxacin,
ampicillin
Methotrexate, etoposide
Topotecan, mitoxantrone,
doxorubicin, daunorubicin
Amfetamines
Amfetamines
Amfetamines, imipramine,
desipramine, clonidine, cimetidine
Metamfetamine, quinidine,
verapamil, pyrilamine
Valproic acid
Unknown
Carbamazepine, primidone

the recent review article by Ganapathy et al.[60] and
workshop report by St-Pierre et al.[61] for a more
detailed examination of all active transporters ex-
pressed in the placenta that are involved, or thought
to be involved, in drug transfer.
2.3.1 P-Glycoprotein
The multidrug resistant gene (MDR1) product, P-
glycoprotein, is a member of the ATP-binding cas-
sette (ABC) transporter family. It has received a
great deal of attention by researchers because of its
recognised importance in the disposition of a wide
variety of drugs. P-glycoprotein consists of two
subclasses, class I (MDR1 in humans, mdr1a and
mdr1b in rodents) and class II (MDR2 or 3 in
humans and mdr2 in rodents).[62] These large multis-
panning membrane proteins (170kDa) are mainly
found in luminal or apical membranes of a range of
epithelia in the body, where they function as ATP-
driven efflux pumps, thereby limiting intracellular
accumulation of xenobiotics.[63] Compounds trans-
ferred by P-glycoprotein are usually uncharged or
basic in nature and can range in size from 200 to
more than 1800Da.[63] The physiological role of
P-glycoprotein is not completely understood, but it
has been postulated that this transporter evolved as a
protective mechanism against the potential toxic

© 2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism
effects of environmental toxins and other xenobiot-
ics.[60] However, in some cells it has been shown to
extrude the natural ligands estradiol-17β-D-glucur-
onide, opioid neuropeptides and platelet-activating
factor.[64-66] Pharmaceutical substrates of P-glyco-
protein are structurally unrelated; they include some
anticancer drugs, immunosuppressive agents, HIV
protease inhibitors, central nervous system active
drugs and cardiovascular drugs.[67-69]
In the placenta, P-glycoprotein is expressed in the
trophoblast cells of the brush-border membrane, but
not the basal membrane.[70,71] Few functional studies
have been carried out to confirm the activity of
P-glycoprotein in the placenta. Ushigome et al.[72]
demonstrated that P-glycoprotein regulates the
transfer of vincristine, vinblastine and digoxin into
trophoblast cells. The fetal-to-maternal transfer of
these drugs across the trophoblast monolayer was
shown to be greater than transfer in the opposite
direction.[72] In the presence of P-glycoprotein in-
hibitors, this transport was reduced, which resulted
in increased fetal uptake.[72] Pávek et al.[73] recently
demonstrated that P-glycoprotein pumps ciclosporin
out of trophoblast cells in the in vitro perfused rat
placenta which restricted the passage of ciclosporin
into the fetal circulation.
The mdr1a (P-glycoprotein) knockout (–/–)
mouse has provided a unique and valuable pharma-
cological tool to examine the function of P-glyco-
protein in various tissues in vivo.[74,75] Lankas et
al.[76] showed that administration of an isomer of the
pesticide avermectin was associated with a 100%
incidence of fetal cleft palate in these mice. Hetero-
zygous (+/–) mice were less sensitive and homozy-
gous (+/+) foetuses, with abundant P-glycoprotein,
were totally insensitive at the doses tested. Further-
more, it was found that the degree of chemical
exposure was inversely related to the expression of
P-glycoprotein, which was determined by fetal gen-
otype.[76] Smit et al.[77] used mdr1a/1b (–/–) mice to
assess the role of P-glycoprotein in fetal toxicologi-
cal protection against digoxin, saquinavir and pacli-
taxel. They found that 2.4-, 7- and 16-fold more
digoxin, saquinavir and paclitaxel, respectively, en-
tered the fetal circulation of mdr1a/1b (–/–) mice
© 2004 Adis Data Information BV. All rights reserved.
497
than wild-type mice.[77] These studies suggest that
P-glycoprotein plays a major fetoprotective role,
although the danger of extrapolation from murine to
human pregnancy should be reiterated.
2.3.2 Multidrug Resistance Protein
Another important group of human ABC trans-
porters is the members of the multidrug resistance
protein (MRP) family.[78] The MRP family consists
of seven members, designated MRP1 to MRP7.[79]
Typically, MRPs are larger (190–200 kDa) than
other ABC proteins, containing about 250 additional
amino acids.[80] MRP1, MRP4 and MRP5 proteins
are widely distributed in the body, whereas MRP2,
MRP3 and MRP6 appear to be mainly expressed in
the liver, kidney and gut.[81,82] MRP proteins media-
te ATP-dependent transport of unconjugated,
amphiphilic anions and of lipophilic compounds
conjugated to glutathione, glucuronate and sul-
fate.[79,83] A wide array of endogenous ligands have
been identified for the MRPs (summarised in recent
reviews by Gerk & Vore and König et al.).[78,84]
Drugs transported by MRPs are the anticancer
agents methotrexate, etoposide, vincristine, vinblas-
tine and cisplatin, HIV protease inhibitors, paraceta-
mol (acetaminophen) glucuronide and the antibac-
terials grepafloxacin and ampicillin.[61,79,84]
In immunohistochemical studies, human placen-
ta at term was found to express at least three mem-
bers of the MRP family: MRP1, MRP2 and
MRP3.[85-87] MRP1 and MRP3 were particularly
abundant in fetal endothelial cells of the placenta
microcapillary.[86] MRP3 was expressed to a lesser
degree in the apical membrane of the syncytio-
trophoblast, and both the presence and absence of
MRP1 in the apical membrane of the syncytio-
trophoblast of term placenta has been reported.[85-87]
MRP2 was detected in the apical membranes of the
syncytiotrophoblast and not in fetal blood ves-
sels.[86] The physiological function of MRP-related
proteins in the syncytiotrophoblast layer remains
speculative, although it seems likely that they could
exert a feto-protective role by the removal of meta-
bolic end products from the foetus to the moth-
er.[86,88]
Clin Pharmacokinet 2004; 43 (8)
498
2.3.3 Breast Cancer Resistant Protein
The ATP-driven breast cancer resistant protein
(BCRP) [also called placenta-specific ABC trans-
porter or ABCP] is also part of the ABC transporter
family and is highly expressed in the placenta.[89] As
yet, its specific localisation in the placenta is un-
known, but is suspected to be on the apical side.
BCRP can render tumour cells resistant to the anti-
cancer drugs topotecan, mitoxantrone, doxorubicin
and daunorubicin.[90] In pregnant mice, it has been
demonstrated that placental BCRP restricts the pas-
sage of topotecan and mitoxantrone to the foetus.[91]
2.3.4 Monoamine Transporters
The three monoamine transporters identified in
the placenta are the serotonin transporter (SERT),
the norepinephrine transporter (NET) and the ex-
traneuronal monoamine transporter (OCT3).[92-94]
SERT and NET are located in the brush-border
membrane of the placental trophoblast where they
transport serotonin and dopamine and norepine-
phrine, respectively, using the transmembrane Na+
and Cl– electrochemical gradient.[92,93] Monoamine
transporters may play a role in maintaining optimal
blood flow to the placenta by controlling the placen-
tal transfer of vasoactive compounds.[92,93] NET, and
to a lesser degree SERT, have been shown to trans-
port amfetamine and its derivatives into the syncyti-
otrophoblast from the maternal side.[95] On the other
hand, cocaine and nontricyclic antidepressants bind
to these transporters with high affinity without being
transferred across the membrane.[93] Moreover, it
has been suggested that cocaine may enhance the
expression of NET in the placenta.[96] It has also
been demonstrated that cannabinoid receptors ex-
pressed in the placenta play a role in the regulation
of SERT activity.[97] Thus, it seems likely that the
use of cannabis during pregnancy could affect the
placental clearance of serotonin via SERT. OCT3 is
thought to be located in the basal membrane where it
actively transports serotonin, dopamine, norepine-
phrine and histamine as physiological substrates via
a Na+ and Cl– independent system.[60,94] Several
drugs, such as amfetamines, imipramine and desi-
pramine, may also be actively transported by pla-
© 2004 Adis Data Information BV. All rights reserved.
Syme et al.
cental OCT3, although further research is needed to
confirm this.[60]
2.3.5 Novel Organic Cation Transporters
The novel Na+-driven organic cation transporter
2 (OCTN2) is expressed in the basal membrane of
the syncytiotrophoblast and transports carnitine
across the placenta from the maternal circulation
into the fetal circulation.[98,99] Placental OCTN2 also
transports metamfetamine, quinidine, verapamil and
pyrilamine, which compete with carnitine for the
transporter, restricting its transfer across the placen-
ta.[99,100] OCTN1 has been found in the rat placenta
and interacts with desipramine, dimethylamiloride,
cimetidine, procainamide and verapamil.[101]
2.3.6 Monocarboxylate Transporters and the
Dicarboxylate Transporter
Monocarboxylates (e.g. lactate) and dicarboxy-
lates (e.g. succinate) are actively transported in the
placenta. Both the monocarboxylate transporters
(MCTs) and the dicarboxylate transporter (NaDC3)
are expressed in the brush border membrane of the
placenta, although MCTs may also be present in the
basal membrane.[102-104] These transporters are elec-
trochemical gradient-driven; MCTs are H+-coupled
and NaDC3 is Na+-coupled.[103,105] Little is known,
however, about the potential of these transporters to
influence drug transfer across the placenta. Valproic
acid is frequently administered for the treatment of
all forms of epilepsy during pregnancy even though
there is a risk of fetal toxicity, including teratogenic-
ity.[106] Although valproic acid, with a pKa of 4.9,
behaves as an anionic ion under physiological pH, it
easily crosses the placenta. Its fetal/maternal blood
concentration ratio is reported to be 1.71.[107] Re-
cently, it has been demonstrated that a saturable
active transport system exists for the uptake of val-
proic acid in the brush-border membrane of tropho-
blast cells.[108-110] This transport system includes an
H+-coupled MCT that causes the high rate of valpro-
ic acid transfer to the foetus across the placental
barrier. Although valproic acid and lactate compete
for the MCT mechanism, valproic acid appears to be
a substrate for more than one transporter.[110]
Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism 499

2.3.7 Sodium/Multivitamin Transporter Table II. Cytochrome P450 (CYP) expression and activity in first-
trimester and term human placenta[6,10,113,116-118,121-123,126-131]
Vitamins biotin and pantothenate are physiologi-
CYP isoenzyme First trimester Term
cal substrates for the Na+-dependent sodium/multiv-
CYP1 1A1 +abc +abc
itamin transporter (SMVT), which is located in the
1A2 +a –ab
brush-border membrane of the placenta.[111,112] 1B1 +a +a
SMVT appears to regulate the maternal-to-fetal CYP2 2A6 – a
–a
transfer of these compounds by pumping them into 2A7 – a
–a
the syncytiotrophoblast from the maternal blood. 2A13 –a –a
There is some speculation that anticonvulsant drugs, 2B6 –a –a
such as carbamazepine and primidone, compete 2B7 –a –a
with biotin and pantothenate for the SMVT trans- 2C +a –a
porter, thus reducing the placental transfer of these 2D6 +a, –c –a, –c
endogenous compounds to the foetus.[60] 2E1 +ab, –/+c +a, –/+bc
2F1 +a +a
CYP3 3A3 ? +a, –b
3. Drug Metabolism
3A4 +ab +a, –/+b,
–c
Although the notion that the placenta acts as a
3A5 +ab +a, –/+b
metabolic barrier to xenobiotics has some attrac-
3A6 +ab +a, –b
tions, it seems that for most drugs placental metabol-
3A7 +ab –/+ab
ism is relatively minor and is not a significant factor CYP4 4B1 +a +ab
in limiting the extent of their passage across the a mRNA.
placenta. In some cases, however, the enzymes acti- b Immunohistochemistry/protein.
vate xenobiotic compounds making them toxic to c Activity.
the foetus.[113] There is scant evidence in the litera- + = detectable; – = undetectable; ? = unknown.
ture for the presence of phase I enzymes in the
placenta other than cytochrome P450s (CYPs) and growth of the foetus, when it is most susceptible to
only a few phase II enzymes have been well charac- the effects of teratogens, the expression of CYP
terised. genes is maximal, while later in pregnancy those
that are not urgently needed for fetal well-being can
3.1 Phase I Reactions
be switched off. With this in mind, Paakki and
CYP enzymes participate in the synthesis and coworkers[123] have recently postulated that mater-
catabolism of steroid hormones as well as nal drug abuse, by serving as an enhancing stimulus,
metabolising vitamins, fatty acids and a wide range might maintain the expression of specific CYP for-
of medicinal drugs and toxic chemicals.[114-116] The ms that would normally be switched off. A variety
placenta contains multiple CYP isoenzymes in the of maternal and environmental factors may affect
mitochondria and endoplasmic reticulum of tropho- the levels of drug metabolising enzymes in the pla-
blastic cells.[10] In the full term placenta, mRNAs for centa. Placental xenobiotic-metabolising activities
CYP1A1, 1B1, 2E1, 2F1, 3A3–7 and 4B1 have been are altered in mothers who abuse drugs, smoke,
detected, but only CYP1A1, 2E1, 3A4, 3A5, 3A7 drink alcohol, are exposed to polluted air or eat
and 4B1 have been characterised at the protein level contaminated food.[121,123-125]
(table II).[10,117,118] The type and amount of ex-
pressed CYPs varies depending on the period of 3.1.1 Cytochrome P450 (CYP) 1 Family
gestation and maternal health status.[119-121] In gener- So far, three members of the CYP1 family have
al, it appears that more CYP isoforms are expressed been detected in the human placenta: CYP1A1, 1A2
in the first trimester than at term.[118,122] It has been and 1B1.[118,126] It is well recognised that CYP1A is
suggested that during the early development and involved in the bioactivation of many compounds,

© 2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (8)
500
such as polycyclic aromatic hydrocarbons, that lead
to adverse effects in the foetus.[10,113] CYP1A1
mRNA, protein and activity have been detected
throughout pregnancy.[117,118] CYP1A2 mRNA has
been detected in the first-trimester placenta, but not
at term.[117,118] Interestingly, there appears to be
greater CYP1A expression in placentas from young-
er mothers.[121] Although CYP1B1 mRNA is ex-
pressed in placental tissue throughout pregnancy,
the impact of placental CYP1B1 in total placental
xenobiotic-metabolising capacity is thought to be
relatively insignificant.[122,132]
The transcriptional inducibility of CYP1 en-
zymes, particularly CYP1A1 and 1B1, is related to
the level and binding affinity of aryl hydrocarbon
(Ah) receptors and Ah receptor nuclear translocator
(ARNT), which have been detected in high concen-
trations (but with considerable interindividual vari-
ability) from the placental cytosolic fraction at
term.[122,132,133] Ah receptor mRNA persists at the
same level throughout the pregnancy, but ARNT
mRNA levels are highest in first trimester sam-
ples.[132] There seems to be a role for constitutive
CYP1A1 in fetal development via the Ah/ARNT
complex, which means that inducers and inhibitors
could potentially interfere with normal fetal
growth.[134]
Cigarette smoking increases xenobiotic-
metabolising CYP1A activities in the placenta to a
variable extent depending on the stage of preg-
nancy.[121,135,136] The induction of placental CYP1A
activity by tobacco smoking in pregnancy, partic-
ularly CYP1A1, is greatest at term, with elevated
levels being sustained for a number of weeks after
smoking is stopped.[127,137,138] Recent data suggest
that smoking and drinking synergistically elevate
placental CYP1A activity.[121]
3.1.2 CYP2 Family
Most studies using specific antibodies and sub-
strates to identify the presence of CYP2A, 2B, 2C,
2D and 2E isoenzymes have yielded negative results
in the placenta.[113,120,121,128] Moreover, CYP2A and
2B mRNA has not been detected in human placenta
at any stage of pregnancy.[118,129] CYP2E1 has been
detected at the level of mRNA and protein from the
© 2004 Adis Data Information BV. All rights reserved.
Syme et al.
first trimester onwards and it has been demonstrated
that ethanol is metabolised to acetaldehyde in the
human placenta.[118,121,139,140] Like CYP1A1,
CYP2E1 levels in the placenta exhibit considerable
individual variation.[141]
3.1.3 CYP3 Family
The CYP3 family is quantitatively and qualita-
tively the most plentiful CYP family in the liv-
er.[114,142] Even though CYP3A mRNAs and proteins
have been detected in human placenta, no relevant
marker activities for CYP3A enzymes (e.g. ster-
oid 6β-hydroxylation) have been reported so
far.[118,120,128,130]
3.2 Phase II Reactions
3.2.1 Uridine
Diphosphate Glucuronosyltransferases
Uridine diphosphate glucuronosyltransferases
(UGTs) are extensively involved in phase II meta-
bolism, where they conjugate glucuronic acid to
xenobiotics.[143] This conjugation is generally con-
sidered to be a detoxification reaction by making the
drug more polar and, thus, more susceptible to ex-
cretion.[143] So far 15 isoforms of UGTs have been
identified which are divided into two subgroups,
UGT1 or UGT2. It is now recognised that UGTs are
present in the placenta throughout gestation and
probably play a major role in placental metabolic
activity.[7,121,144,145] Recent studies have detected
mRNA and protein expression of the UGT2B iso-
forms (UGT2B4, 2B7, 2B10, 2B11, 2B15 and
2B17) in the syncytium of both first trimester and
term placentas.[7,121,145] UGT1A mRNA and protein
expression have been detected in the first-trimester
placenta, but have been undetectable at term.[7,121]
Significant UGT activity towards marker substrates
has been demonstrated in placenta in the first trimes-
ter and at term.[7,121,146,147] For example, Schenker et
al.[147] found that 17% of olanzapine, on average, is
converted to the glucuronide, which is transferred
by the placenta at a rate slightly slower than the
parent drug. However, there appears to be high
interindividual variation in UGT expression and ac-
tivity in the human placenta.[7,123,146] A recent study
has demonstrated that placental UGT activity is
Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism
elevated by maternal smoking and is greatest in
mothers who both smoke cigarettes and drink alco-
hol.[121]
3.2.2 Glutathione S-Transferases
Glutathione S-transferases (GSTs) catalyse the
conjugation of glutathione to biologically active
electrophiles. Placental GST is very active through-
out pregnancy.[8,127,128] Hence, GSTs may play a key
role in protecting the foetus against electrophiles or
oxidative stress. So far, however, GST activity in the
placenta has been related to hormone metabolism
rather than detoxification of xenobiotics.[127]
In mammals, four classes of GSTs have been
identified: α, μ, π and θ.[148] Isoenzyme π, or
GSTP1-1, is the only form of GST that has been
purified and cloned from human placenta.[149,150] It is
evenly distributed among cell types in the placenta
and accounts for 85% of total GST activity, the
remainder being of unidentified composition.
3.2.3 Epoxide Hydrolase
Epoxide hydrolase is present in a variety of
organs throughout the body where it catalyses the
conversion of epoxides into transglycols or trans-
dihydrodiols.[9] Only one form of epoxide hydrolase
has been found in the human placenta, being detect-
able from 8–9 weeks of gestation onwards.[9] Al-
though well-known epoxide derivatives of pheny-
toin and valproate are recognised for their ability to
produce birth abnormalities when administered to
pregnant mothers, it has been demonstrated that
placental epoxide hydrolase contributes very little to
these adverse outcomes.[151]
3.2.4 Sulfotransferases
Sulfotransferases are of great importance in the
sulfate conjugation of steroids and catecholamines
in human tissues, including the placenta, but little is
known about their involvement in placental drug
metabolism. High levels of sulfated steroids and
catecholamines are present in plasma; more than
90% of dopamine in plasma exists in the sulfated
form.[152] In humans, ten sulfotransferase genes are
known, one of which encodes two different enzyme
forms.[153] So far, it appears that many of these
isoforms are expressed to some degree in the placen-
© 2004 Adis Data Information BV. All rights reserved.
501
ta.[154-156] Sodha et al.[157] compared the sulfate con-
jugation of the β2-adrenoceptor agonists salbutamol
(albuterol), ritodrine and fenoterol with that of dop-
amine using in vitro placental tissue and found that
although the rate of formation was slower, the de-
gree of conjugation was similar for this group of
drugs as it was for dopamine. The in vitro activity of
sulfotransferase in the placenta towards the anthel-
mintic betanaphthol was about 1% and 8% of that in
the adult and fetal liver respectively.[158] Another
marker substrate, paracetamol, was not found to be
sulfated in the isolated perfused human placenta.[159]
These results suggest that sulfation in the placenta
may be a significant biotransformation pathway for
some drugs.
4. Models to Study Drug Transfer
and Metabolism
The potential for placental drug transfer and met-
abolism provides researchers with extensive and
complex questions when giving drugs to pregnant
women. Much of the information regarding drugs in
pregnancy is derived from animal studies. However,
there are anatomical, morphological and functional
differences among the different types of placentas
found across mammalian species which has pre-
cluded the general extrapolation of these results to
humans.[160-162] During the past 25 years, in vitro
techniques have been developed to study the placen-
tal transfer and metabolism of drugs using human
placenta and some clinical trials have been conduct-
ed in pregnant women.[19]
4.1 In Vitro Models
Several models for studying the placental transfer
and metabolism of nutrients, drugs and toxic chemi-
cals in vitro have been established. These include:
(i) perfused placental cotyledon; (ii) villus explants
and monolayer cultures; (iii) isolated trophoblast
plasma membrane; and (iv) isolated transporters and
receptors. These models resolve some of the ethical
and methodological problems encountered with in
vivo studies, but are not without limitations. The
downside of any in vitro study of placental transfer
and metabolism is that extrapolation of results to the
Clin Pharmacokinet 2004; 43 (8)
502
pregnant woman can be problematic. In vitro mod-
els cannot fully account for all the physiological and
biochemical variables in the mother, placenta and
foetus and how these variables change throughout
gestation.
4.1.1 Perfused Placental Cotyledon
The perfusion of isolated human placental
cotyledon was first described in 1967.[163] The tech-
nique has been modified and well validated in stud-
ies of the transfer of several different endogenous
and exogenous substances.[164-166] It has also been
used successfully to measure the effect of drugs on
placental vascular resistance and the formation of
endogenous compounds by the placenta.[167,168] For
a comprehensive description of this model, readers
are referred to review articles by Sastry and Bourget
et al.[43,52] Experiments can either be conducted us-
ing the closed (recirculating) method or the open
(single pass or nonrecirculating) method. In the
closed model, both the maternal and fetal perfusates
are recirculated which is useful for studying the
transplacental transfer and formation of metabolites.
In the open model, a period of equilibration allows
the perfusate to reach steady state and maternal-fetal
and fetal-maternal clearance can be calculated from
a simple equation. Placental perfusion is the method
of choice for studying placental transport and
pharmacokinetics. However, perfusion systems
clearly require careful validation before they are
routinely used to predict placental drug transfer in
pregnant women.[44]
4.1.2 Tissue Culture
The various types of preparations in this category
include: (i) placental slices or villus explants; (ii)
dispersed syncytiotrophoblastic monolayer cultures;
(iii) trophoblast-derived cell lines; and (iv) microvil-
lus membrane vesicles. Subcellular fractions (e.g.
microsomes) have also been prepared and
used.[52,169,170] These models are useful for investi-
gating the presence of transport systems and
metabolising enzymes in the placenta. Placental ex-
plants offer the advantage of intact microarchitec-
ture and maintenance of cell-cell interactions and
paracrine communications; hence the contribution
of mesenchymal and endothelial cells to any meta-
© 2004 Adis Data Information BV. All rights reserved.
Syme et al.
bolic processes can be taken into account. Tropho-
blast cultures are readily prepared from term placen-
ta and may be allowed to differentiate in culture to
model syncytiotrophoblast function, although mon-
olayer cultures do not readily lend themselves to
transport studies. Recently, however, a method for
preparing and maintaining tight-junctioned syncyti-
um on semipermeable membrane has been de-
scribed, although no studies of drug metabolism or
transport have yet been carried out using this proce-
dure.[170]
Human placental choriocarcinoma cells (e.g.
BeWo, JAr and JEG cells) share many properties
with villus trophoblasts in terms of morphology,
biochemical markers and hormone secretion.[171]
These cells are commonly used for studies of the
placental barrier, including transport mechanisms.
For example, a recent study using a BeWo monolay-
er demonstrated that both endogenous and synthetic
opioid peptides cross the placenta via a paracellular
route and that endogenous, but not synthetic, pep-
tides are metabolised by placental aminopep-
tidase.[172]
4.2 In Vivo Models
Any in vivo study of the placental transfer and
metabolism of a substance must take into account
ethical aspects linked to the study of metabolic
processes in pregnant women. The tragedy of thalid-
omide serves as a constant reminder. This event and
several others have led to the adoption of rules
governing clinical trials in humans. Pregnant
women are usually excluded from clinical trials
unless a direct benefit is expected. It is easy to
understand why pharmaceutical companies gen-
erally label drugs as contraindicated or nonapproved
for pregnant women when any harm to the foetus
will cause widespread condemnation and crippling
lawsuits.
The fetal/maternal blood drug concentration ratio
is used as the simplest index for placental transfer in
vivo. This is often calculated from blood samples
taken from a peripheral vein (maternal blood) and
from the umbilical cord (fetal blood) at the time of
placental expulsion.[51,173] Many studies have esti-
Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism
mated the extent of maternal-to-fetal drug transfer
by comparing the concentrations of drug in maternal
blood to those in fetal blood samples after adminis-
tration of a single dose of drug to the mother. Some
studies have used single pairs of samples to estimate
maternal/fetal drug disposition, but this may not be a
reliable estimate. The fetal/maternal concentration
ratio may vary widely in pairs of samples after
administration of a single maternal dose. More
meaningful information about drug distribution be-
tween maternal and fetal circulations can be pro-
vided by maternal drug infusions, beginning with a
loading dose to maintain a constant maternal drug
concentration. The most accurate assessment also
requires the comparison of unbound drug concentra-
tions during sustained maternal steady-state condi-
tions. However, measurement of unbound drug con-
centrations often requires larger samples of blood
and obtaining these from a foetus may be unethical
and dangerous.
The anatomical and functional differences be-
tween mammalian placentas frequently compromise
the translation of results of placental drug transfer
and metabolism from animals to humans. Especially
for hydrophilic molecules, placental permeability
varies widely among species.[174] The observed spe-
cies differences are predominantly a reflection of
structural differences. The higher permeability of
the human and guinea pig placenta to hydrophilic
molecules, compared with the sheep, may be due to
the former having less tissue layers separating the
maternal and fetal bloodstreams.[175,176]
Non-human primates, such as rhesus macaques
and baboons, are sometimes used in placental trans-
fer experiments to provide a close-to-human
model.[177] For example, recently researchers suc-
cessfully used rhesus monkeys to deliver a transgene
to the placenta in vivo via a lentiviral vector.[178] In
another study, rhesus macaques were used to mea-
sure the transplacental transfer of stavudine, an anti-
HIV compound, and its active and inactive metabo-
lites.[179] The researchers measured significant con-
centrations of both stavudine and its inactive metab-
olite in fetal plasma, but no active phosphorylated
metabolites were detected. Other researchers have
© 2004 Adis Data Information BV. All rights reserved.
503
correlated results obtained in the perfused human
placenta in vitro with those from pregnant macaques
given the anti-HIV drugs zidovudine, didanosine,
zalcitabine and stavudine.[180] They found that the
placental transfer rate and extent in live primates
strongly correlated with those observed in the in
vitro perfused human placenta.
5. Clinical Significance of Placental
Transfer and Metabolism
Over recent years there has been a gradual rise in
the use of pharmaceuticals during pregnancy.
During pregnancy, the most widely taken classes of
drugs are analgesics, antiemetics, antibacterials,
tranquillisers, antihistamines and diuretics.[181,182] In
some cases, such as epilepsy or diabetes, the mother
is continuously exposed to drugs during pregnancy
based on the premise that the benefit to the mother
outweighs the risk to the foetus. Drugs used to
inhibit (e.g. indometacin, nifedipine or salbutamol)
or stimulate (e.g. oxytocin) uterine contractions are
examples of drugs administered near the end of
pregnancy. Fetal therapy via maternal drug adminis-
tration, such as the use of synthetic glucocorticoids
to induce fetal lung maturation in preterm labour,
will probably be employed to a greater extent in the
future. Taken together, this means that an under-
standing of placental transfer and metabolism of
drugs has significant clinical relevance for both
maternal and fetal welfare and may, in some cases,
prove to be a balancing act of risk versus benefit.
The direct effect of a drug on the foetus is depen-
dent on the concentration of drug in the fetal circula-
tion. Prior to delivery, drug measurements can be
obtained from the foetus only by umbilical blood
sampling. However, there are potential risks of fetal
sampling, so this procedure is generally not permit-
ted for evaluating fetal drug exposure alone. The
major determinant of fetal drug concentration is the
maternal drug concentration.[51] As maternal con-
centration is a function of the dose administered,
estimation of the fetal exposure can be based on
maternal drug intake. To determine this relationship,
it is also necessary to know the rate and extent to
which the drug crosses the placenta. Using the con-
Clin Pharmacokinet 2004; 43 (8)
504
centration-time course of the drug in the mother as
the starting point, the concentration in the foetus can
be determined from the placental transfer rate and
the rate of elimination by the foetus.[20]
Cigarette smoke is one of the most widely used
harmful substances to which pregnant women are
exposed.[183,184] It is well established that maternal
smoking has a detrimental effect on fetal growth, but
the mechanisms underlying these effects are not
well understood.[183,184] Smoking has been shown to
alter the structure and function of human placental
tissues, such as the sodium-dependent active trans-
port of alanine, decreasing the capillary volume and
increasing the thickness of the trophoblastic lay-
er.[185,186] It is very difficult to associate specific
compounds in cigarette smoke with negative effects
because there are more than 2000 compounds in the
smoke. Nicotine is one of the principle alkaloids of
tobacco smoke and it has been shown to induce
skeletal, limb and palate malformations in ani-
mals.[187] Exposure of the human foetus to nicotine
is associated with changes in fetal heart rate and
breathing movements.[188,189] Pastrakuljic and col-
leagues[190] confirmed that nicotine readily crosses
the placental barrier but found no evidence of the
nicotine metabolite cotinine in intact placental tissue
or in microsomal fractions. This contradicts pre-
vious reports that the placenta serves as a metabolic
barrier to nicotine.[191]
In 1980, the first reports of transplacental treat-
ment of fetal supraventricular tachycardia by mater-
nal administration of cardiac glycosides opened the
possibility of avoiding iatrogenic premature deliv-
ery by successful cardioversion in utero.[192]
Supraventricular tachycardia (>180 beats/min) is a
potentially life-threatening condition and is the most
common fetal arrhythmia that requires treatment
before birth.[193,194] If the foetus is sufficiently ma-
ture, delivery is an option, otherwise transplacental
drug monotherapy is usually the initial treatment of
choice. Antenatal therapy in preterm pregnancies
consists of the maternal administration of digoxin,
sometimes combined with flecainamide, ami-
odarone or other antiarrhythmic agents.[195] The
treatment success rate of digoxin monotherapy is
© 2004 Adis Data Information BV. All rights reserved.
Syme et al.
about 50%.[196] In adults, digoxin has a narrow ther-
apeutic range (0.5–2.0 μg/L) which makes know-
ledge of its placental transfer vital when treating the
foetus. According to various reports, the fetal/mater-
nal digoxin concentration ratio ranges from 0.1 to as
high as 0.9.[197-201] It appears that the concentration
ratio of digoxin depends on a dynamic balance be-
tween diffusion and active transport systems.[197-199]
Digoxin has been shown to be a very good P-
glycoprotein substrate both in vitro and in
vivo.[69,72,77]
Multidrug therapy including digoxin may give
rise to significant drug interactions in the placenta,
affecting the fetal tissue concentrations of the drugs
and treatment outcomes. For example, digoxin and
verapamil are often coadministered if the initial
digoxin monotherapy fails. In the treatment of fetal
tachyarrhythmia, coadministered verapamil may en-
hance digoxin transfer into the foetus by blocking
placental efflux by P-glycoprotein.[72] This suggests
the possibility that pharmacological manipulation of
placental P-glycoprotein is a potential option to op-
timise pharmacotherapy for fetal tachyarrhythmias.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
are one of the most common classes of medication
prescribed by general practitioners worldwide and
have been administered in pregnancy for the preven-
tion of preterm labour.[202,203] Pregnant women fre-
quently report that they have been taking these drugs
despite their potential to cause adverse effects in the
foetus.[204-206] Animal experiments have linked
NSAIDs to teratogenicity and other adverse effects
in the foetus.[207-209] However, human data concern-
ing adverse effects in the foetus are less conclusive;
there is contradictory opinion regarding the effects
of NSAIDs on birth outcome.[204,205,210] The NSAIDs
tested using human in vitro placental perfusion ex-
periments, such as diclofenac, sulindinac and in-
dometacin, cross the placenta and reach significant
concentrations in the fetal perfusate.[211-213] Newer
cyclo-oxygenase-2 (COX-2) selective NSAIDs,
such as celecoxib and rofecoxib, are being consid-
ered as potential tocolytics for the prevention of
preterm birth.[214,215] NSAIDs have been shown to
cause the premature closer of the fetal ductus arteri-
Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism
osus as well as neonatal renal failure, but these
adverse effects appear to be less common when
using COX-2 specific NSAIDs.[216-218] COX-2 ap-
pears to be an important enzyme in fetal develop-
ment in mammals, and consequently COX-2 selec-
tivity may not offer any advantages over non-selec-
tive NSAIDs.[219-221] Evaluation of the human
placental transfer of COX-2 specific inhibitors may
help to establish if these represent the safest group of
NSAIDs for future clinical studies as therapeutic
agents during pregnancy.
Infants born to mothers with HIV infection who
are receiving antiretroviral therapy have approxi-
mately a 25% chance of becoming infected them-
selves.[222] Antiretroviral drugs are administered
both for direct maternal benefit and for the preven-
tion of mother-to-child transmission. The reduction
of maternal plasma viral load is an important way of
decreasing the risk of HIV transmission to the child,
and drugs that remain in the maternal compartment
would obviate the concern over fetal exposure to
toxic effects.[223] However, preloading the infant
before birth with effective anti-HIV drugs might
have an important prophylactic effect. The HIV
reverse transcriptase inhibitor zidovudine is already
used according to this rationale.[224] The high pla-
cental transfer rate of zidovudine and other reverse
transcriptase inhibitors has been established, and
carries both risks and benefits for a foetus of an
HIV-positive mother.[225] In contrast, the HIV prote-
ase inhibitors, which are generally considered to be
more effective drugs, do not appreciably cross the
placenta.[226-228] Placental P-glycoprotein is prob-
ably an important factor in this low penetration. One
study has shown intravenous administration of sa-
quinavir to pregnant mdr1a/1b knockout mice re-
sults in seven times more drug entering fetal circula-
tion than when the drug is given to wild-type mi-
ce.[77] Moreover, administration of P-glycoprotein
blockers to wild-type mice could completely inhibit
placental P-glycoprotein activity towards sa-
quinavir.[77] These results suggest that it may be
worthwhile to examine the coadministration of ef-
fective P-glycoprotein inhibitors with saquinavir
(and possibly other HIV protease inhibitors) during
© 2004 Adis Data Information BV. All rights reserved.
505
the late stages of pregnancy, in order to increase
infant loading with the drugs. As with other HIV
protease inhibitors, the safety profile of saquinavir
during fetal development is known only from
preclinical animal reproductive studies. There is evi-
dence that fetal hepatic microsomes may be partic-
ularly sensitive to this family of drugs.[229]
Cisplatin is a well-known anticancer drug with
high efficiency against several solid tumours. Re-
cently, it was discovered that by coupling cisplatin
to a bile acid moiety the resulting drug, Bamet-R2,
was less permeable across the rat placenta in
vivo.[230] The ability of the placental barrier to pro-
tect the fetal compartment from cisplatin when it is
coupled to cholylglycinate is probably due to the
existence in the plasma membrane of the trophoblast
of carrier proteins able to transport bile acids from
the foetus to the mother.[231] This research suggests
the potential usefulness of Bamet-R2 as an alterna-
tive anticancer drug in the treatment of certain
tumours during pregnancy.
The maturational effects of corticosteroids on the
foetus were first described in 1969.[232] Since then,
maternally administered dexamethasone or be-
tamethasone have been shown to facilitate fetal lung
maturation, thus reducing the incidence of neonatal
respiratory distress syndrome in premature in-
fants.[233,234] Dexamethasone treatment also results
in enhanced maturation of the fetal brain, heart,
kidney and gastrointestinal tract.[235] Its use is asso-
ciated with a reduced incidence of periventricular
haemorrhage, necrotising enterocolitis, neonatal
death and duration of hospital stay.[236] The signif-
icant healthcare implications of antenatal cortico-
steroid therapy resulted in recommendations by the
US National Institutes of Health for their routine use
at gestational ages of 24–34 weeks when preterm
delivery is anticipated.[237] Since then, there has
been a dramatic increase in the use of antenatal
corticosteroids.[238,239] However, dexamethasone has
a number of potentially serious adverse effects such
as hypertension, adrenal suppression, pneumotho-
rax, hyperglycaemia and increased risk of sepsis.
The placental transfer of dexamethasone appears to
be rapid, as measured in animals and in isolated
Clin Pharmacokinet 2004; 43 (8)
506
perfused human placenta, and it also appears to
undergo extensive placental metabolism.[47,240-243] It
has been suggested by Varma et al.[241] that the
dexamethasone serum gradient observed in rats is
caused by its active transport from the fetal to the
maternal side. Dexamethasone is a substrate for
P-glycoprotein, which pumps this drug out of the
brain and other tissues throughout the body.[69,244-246]
Therefore, it may be that that maternal/fetal concen-
tration ratio across the placenta hinges on a balance
between passive diffusion and affinity for P-glyco-
protein-mediated efflux.
The development of successful strategies for de-
livering genes across the placenta may offer novel
therapeutic options for the foetus. Various investiga-
tors have considered fetal gene therapy for inherited
disorders that cause fetal damage.[247] For example,
viral vectors are being developed that target tropho-
blastic cell types for the treatment of choriocarci-
noma.[248] Recently, the isolated perfused human
placenta was used as a model to assess the feasibility
of transferring genes to trophoblastic tissue.[249] The
researchers found that they were able to effectively
transfect the perfused human placenta with ade-
noviral vectors and the expression of the transgene
was detected in trophoblastic cells. For a variety of
reasons, prenatal gene therapy may be an attractive
possibility that can overcome some of the conditions
limiting gene therapy in adults or children. The
trophoblast escapes some components of host im-
munity that limit viral-based gene therapy in other
target tissues.
6. Drugs of Abuse
For decades, pregnant opioid-dependent patients
have almost invariably been treated with metha-
done. However, maternal methadone significantly
transfers across the placenta and can induce with-
drawal symptoms in the newborn.[250] Bupre-
norphine is an attractive alternative for maintenance
therapy of opioid dependency because in most pa-
tients it produces limited withdrawal symptoms, re-
sults in reduced self-administration of heroin and
has a longer duration of action.[251-253] A recent study
has assessed the placental transfer of buprenorphine
© 2004 Adis Data Information BV. All rights reserved.
Syme et al.
in the perfused human placenta in vitro to help
determine its potential for the treatment of pregnant
opioid addicts.[45] Although buprenorphine is highly
lipophilic, less than 10% of the maternal dose was
transferred to the fetal circuit because the placenta
acts as a depot for the drug. This finding is consis-
tent with the relatively low incidence of neonatal
withdrawal reported after buprenorphine use during
pregnancy.[254,255]
It is well recognised that maternal use of drugs of
abuse such as cocaine and amfetamines during preg-
nancy has adverse effects on the developing foe-
tus.[256] The interaction between these drugs and
placental monoamine transporters may be a possible
cause of these effects.[256] Various mechanisms have
been suggested to describe the interaction of
abusable drugs with these transporters. For example,
the norepinephrine transporter (NET) transfers
metamfetamine into the syncytiotrophoblast of the
placenta.[95] This causes competition between
metamfetamine and norepinephrine for the trans-
porter, resulting in suboptimal transfer of the physi-
ological substrate. The reduction in clearance of
serotonin and norepinephrine from the maternal
blood by drugs competing with their respective pla-
cental transporters will increase their concentration
and could cause vasoconstriction of the uterine ar-
teries and decreased blood supply to the placen-
ta.[256-258] This will, in turn, reduce the supply of
oxygen and nutrients to the foetus. It has also been
suggested that elevated levels of norepinephrine
may increase the incidence of premature delivery by
inducing myometrial contractile activity.[256-258]
Cannabis is one of most widely abused drugs
during pregnancy; a recent British survey found that
5% of pregnant mothers smoked cannabis before
and/or during pregnancy.[259] Δ9-Tetrahydrocan-
nabinol (THC) is the major psychoactive component
of cannabis. THC exposure during the first 2 weeks
of pregnancy has been associated with embryocidal
effects in mice, as well as reduced fetal
bodyweight.[260] In humans, THC has not been relat-
ed to prenatal death but may cause a small reduction
in birthweight.[259] Moreover, prenatal THC expo-
sure has been correlated with altered behaviour in
Clin Pharmacokinet 2004; 43 (8)
Placental Drug Transfer and Metabolism
these children such as hyperactivity, inattention and
impulsivity.[261,262] As would be expected from its
high lipophilicity, THC rapidly crosses the mouse,
sheep and monkey placenta in vivo; peak concentra-
tions in the primate foetus occur within 15 minutes
of a maternal intravenous injection.[260,263,264] In
pregnant women who smoked cannabis daily, THC
was detected in umbilical cord blood at concentra-
tions 2.5–6 times lower than in maternal blood at the
time of delivery.[265]
7. Conclusion
An understanding of the degree of fetal exposure
to a drug is an important aspect of pharmacological
treatment of pregnant women. Almost all drugs
cross the placenta by passive diffusion and some
reach pharmacologically significant concentrations
in the foetus. An increasing number of active trans-
porters have been found that are involved in placen-
tal drug transfer both to and from the foetus. This
raises the possibility of interactions when drugs
compete for the same transporter or inhibit its nor-
mal functioning. Moreover, there is the concern that
drugs interfere with the active transport of endoge-
nous compounds essential to fetal development.
Sound knowledge of the transfer and metabolism of
a drug across the placenta can help distinguish be-
tween drugs that readily cross the placenta and ex-
pose the foetus to significant concentrations and
drugs that are blocked or metabolised sufficiently by
the placenta to negate the concern of fetal exposure.
This understanding will hopefully improve the ef-
fectiveness and safety of drug administration in
pregnancy, allowing existing drugs of possible ther-
apeutic benefit to be administered during pregnancy
without risk to the foetus, while realising the poten-
tial of pharmacological treatment of the foetus.
Acknowledgements
Financial assistance was received from the Maurice and
Phyllis Paykel Trust and Uniservices Limited. There are no
conflicts of interest directly relevant to the content of this
review.
© 2004 Adis Data Information BV. All rights reserved.
507
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Correspondence and offprints: Dr Jeffrey A. Keelan, Division
of Pharmacology and Clinical Pharmacology, Faculty of
Medical and Health Sciences, University of Auckland, Pri-
vate Bag 92019, Auckland, New Zealand.
E-mail: j.keelan@auckland.ac.nz
Clin Pharmacokinet 2004; 43 (8)