PHARMACOKINETICS II

(An idea on drug

distribution, metabolism and
excretion with traditional views.)

Dr. K.J.Karthika,
Final year P.G scholar.
Department of R&B,
GAVC, Tripunithura.

Contents

Diffusio
n

Tissue
perfusio
n

Drug
distribut
ion

Plasma
protein
s

Cardiac output
Regional blood flow
Capillary permeability
Tissue volume

Factors
controlli
ng drug
distributi
on

Pshysico
chemical
propertie
s of drugs

Physiologi
cal factors

Cardiac output
Regional blood
flow
Capillary
permeability
Tissue volume

Drug administration
Partition of drug b/w blood and body tissue
based on.
- Transmembrane pH
- Lipid solubility
Initial distribution to well perfused
organs(heart, liver, kidney, brain,etc)
second phase distribution to large fraction of
body mass like muscle, skin, fat etc.(greater
time needed to reach equillibrium state)

Diffusion
Drug
absorption
administration.

or

systemic

Diffusion
to
interstitial
intercellular fluid.

or

Plasma protein and drug

distribution
- Albumin Majorly binds with acidic
drugs.
- 1 acid glycoprotein binds with
basic drugs.
- Non specific binding forming
irreversible
covalent binding of
reactive drugs like alkylating agents.
- Specific binding sex hormone
binding globulin for oestrogen and
testosterone.

The bound unbound drug

concentration is
determined
by
- Affinity of binding sites.
- Number of binding sites.
Existinc
Pathology
eg;
liver
diseases, nephrotic syndrome causes
hypoalbuminemia.
cancer, arthritis, MI, Crohns disease
elevate
1 acidglycoprotein
enhancing binding of basic drugs.
Drug- drug interaction competition
or
site, alteration of physiology, etc.

Effects of protein binding.

Limits drug concentration in tissues and site of
action.
Only the unbound drug is in equilibrium across
the membranes.
limits the drugs glomerular filtration.
Drug transport
limited.

and

metabolism

are

also

Tissue concentration of drugs

-Many drugs accumulate in the tissues at higher
concentrations than those in extra cellular fluids
and blood.
-Eg.
antimalarial
drug
quinacrineliver
concentration may exceed several thousand
times than blood concentration.
-The tissue concentration build up can be due to.
Active transport
Tissue binding( mostly reversible) to
- Proteins
- Phospholipids
- Nuclear proteins, etc

Effects
of
tissue
concentration
of
drugs
local drug toxicity
Gentamicin
in
kidney
vestibular system.

e.g;
and

Cellular reservoirs
- Fat
- Bones
- Trans cellular fluid
- Sites with active transport of
drugs and tissues with affinity to
drugs. Vary with the type of drug.
Eg, liver, kidney, etc

Fat as reservoir
-Many lipid soluble drugs are stored in
by physical solution in neutral fat.
-A stable reservoir due to relatively low
blood flow.
Difficulty to predict lipophilic drug
distribution in obese individuals.
Eg, blockers, barbiturate thiopental.

Bone:
Tetracycline antibiotics and heavy metals adsorb
onto bone surface and eventually to crystal
lattice.
Reservoir for slow release toxic agents e.g. lead
or radium .Their effects persist long after their
exposure has stopped.

Therapeutic advantages:
Treatment of osteoporosis by
phosphonates
like
sodium
etidronate which is resistant to
pyrophosphatases
enzyme
thus stabilizes bone matrix.

Transcellular fluid reservoir:

Drugs cross the epithelial cells and
accumulate in the transcellular fluids.
The major trans cellular reservoir being
the gastrointestinal tract and others are
CSF, aqueous humor, endolymph, synovial
fluid,etc.
The
levels
significant.

accumulated

are

not

Redistribution
The redistribution from site of action to
other sites cause termination of drug effect
before drug withdrawal.
Primarily seen when a highly lipid soluble
drug that acts on brain or cardiovascular
system
is
administered
rapidly
by
intravenous injection or inhalation.
As the I V administration is ceased once
attaining the peak concentration in the
desired tissue, the drug diffuses to other
tissues
like
muscles.
Gradually
the
concentration in desired tissue falls to match

CNS and
fluid.

cerebro

spinal

-Factors preventing transport of drug to

brain
1. BBB (brain capillary endothelium and
pericapillary glial cells)
2. Blood CSF barrier (at choroid plexus
where epithelial cells are joined by tight
junctions.)
Drug penetration into the brain depends
on trans-cellular transport.

Essential factors for

uptake of drug by
brain.
Lipid soluble


Meningeal
inflammation
permeability.

and
encephalic
increases
local

Recently BBB destruction has

emerged
as
a
strategy
in
treatment of certain brain tumors
where the intention is to directly
deliver the chemotherapy agent
to
the
brain
tumor
while
maintaining the cognitive function
that
is often damaged by
conventional radiotherapy.

Volume of Distribution:
-Relates to the amount of drug in the body
to the concentration of drug in blood
/plasma depending on the fluid volume.
The blood plasma volume of a 70kg man
is considered to be 3l
blood volume is 5.5l.
The extracellular fluid volume 12l
total body water is 42l.

The
volume
of
drug
distribution depends on:
pKa of drug
the degree of binding to plasma
proteins
partition coefficient of drug in
fat.
Degree
tissue.

of

binding

to

other

Ayurvedic aspects

rug Metabolism

Drug metabolism
Phase 1- functionalization

introduce a functional
group
to
parent
compound.
Loss/
alteration
pharmacological
activity.

of

Enzyme
system
located
mainly
in
endoplasmic
reticulum.

Pase 2- biosynthetic reaction

Formation of covalent
linkage between the
functional
group
of
phase 1 metabolite and
endogenously
derived
glucuronic
acid,
sulphate,
glutathione,
amino acids or acetates.
>> Actively excreted.
Enzymes mainly located
in Cytosol.

Site for biotransformation (location):

Mainly liver
GIT
Kidneys
Lungs

Cell organelles involved

Mainly smooth endoplasmic reticulum

Cytosol
Mitochondria
Nuclear envelope
Plasma membrane.

Systems involved in drug

metabolism
Cytochrome
P450
oxygenase system.
hydrolytic enzymes.
conjugation reactions.

mono

system
-Heme containing membrane protein found in
smooth endoplasmic reticulum of numerous
tissues.
-catalyzes wide range of oxidative and reductive
reactions.
-the xenobiotic substrates reacts with the Fe3+ of
the cytochrome P450 and form enzyme substrate
complex and thereafter further reactions of
biotransformation proceeds. Electons from NADPH
is utilized by it.
- 12 gene families have been identified for
cytochrome P450 enzyme and a number of

Hydrolytic enzymes:
- Found in endoplasamic reticulum of
human liver intestine and other tissues.
- The alcohol and amine group exposed
following the hydrolysis of esters and
amines are the substrates.

Conjugation Reactions
- Hallmark of phase 2.
- Most significant is glucuronidation
following which there is increased water
solubility and promotes drug elimination
through urine.
- conjugation of electrophilic metabolites of
xenobiotics with tripeptides of glutathione
is the major detoxification pathway for
drugs and carcinogens.

Factors
effecting
metabolism

drug

Genetic variation:
-For an increasing number of enzymes
allelic variants with different catalytic
activities have been identified.
-The differences involve a
molecular mechanisms leading
lack of activities, a reduction
ability or in case of gene
enhanced activity.

variety of
to complete
in catalytic
duplication

Environmental
determinants:
The activity of most of the drug
metabolizing enzymes may be
modulated by exposure to certain
exogenous compounds. These may
result in :Inhibition of drug metabolism
Inuction of drug metabolism

Disease factors:

- Hepatitis , alcoholic liver disease,

biliary
cirrhosis,
fatty
liver
and
hepatocarcinoma can potentially lead
to impaired drug metabolism.
- The oral availability of drugs that
undergo first pass metabolism and
reduced bioavailability is increased 2-3
fold.
- Severe cardiac failure and shock can
result in both decreased perfusion of
liver and impared metabolism.

Age and sex:

Cytochrome P450 isoforms develop early in
foetal development but levels at birth are lower
than those found post natal.
Both phase 1 and phase 2 enzymes begin to
mature gradually following the first two to 4 wks.
Thus newborn infants are able to metabolize
drugs but slower than adults.
Elderly generally requires moderate reduction in
drug dose and awareness of possibility of
exaggerated pharmacodynamic responsiveness.
Responsiveness of men and women may be
different for certain drugs. some sex related

Drug Excretion

Excretion of drugs
Drug is
excreted as

Unchang
ed form

metabolite
s

Polar compounds excreted more efficiently than the lipid

soluble drugs.

Renal
(mutr
a)

swea
t

Routes
for

drug
saliv
a

excretio
n

Brea
st
milk

Biliar
y and
fecal
(sakr
ut)

tear

Renal excretion
Involve 3 distinct process
Glomerular filteration
Tubular secretion
Tubular reabsorption
Age and renal function
Neonates low renal function low in the
beginning which matures rapidly.
In adulthood the renal function gradually
declines approx 1% per year.
Elderly- substantial rate of renal impairment.

entry to tubular lumen

GFR
Extend of plasma binding(unbound
drug filtered)
Carrier mediated tubular secretion
in PCT
Reabsorption
by
membrane
transport at DCT
Passive reabsorption non ionized
forms of wk acids and bases in PCT
and DCT
pH of urine( alterations can result
in significant change in drug

 sweat
saliva- some drug concentration here
parallels plasma concentration thus
can be collected when inconvenient
to collect blood. Ethanol n urea
readily enters B.M.
tears
breast milk- slightly more acidic
than plasma basic compounds may
be accumulated
Elimination by these routes depends
mainly on diffusion of non-ionized lipid

Biliary and fecal

excretion

Absorption

from
intestine
for
hepatic clearence

Secretory transporters on the apical

membrane of enterocytes causes
direct
secretion
of
drugs
and
metabolites to the intestinal lumen.

transporters present in the

canalicular membrane of
hepatocytes actively secrete
drugs and metabolites into
the bile

It is the term used to indicate the fractional

extend to which a dose of drug reaches its site of
action.
The bioavailability depends on
Nature of drug
Route of administration.
Anatomical site from which absorption takes
place
Other
anatomical,
physiological
and
pathological factors.
When the hepatic Clearence of the drug is more
in relation to the hepatic circulation the
bioavailability of drug when orally administerd

In Ayurveda
More biovailability is possibly be in
the order
1. Basthi prayoga.
2. Oral intake
3. Abhyandadi bahya prayoga
4. Nasya
5. Nethra kriyakrama

THANK YOU