6/2/2020 Passage of drugs across membranes - Pharmacorama

Home Ezine Pharmacology Quizz

Custom Search Search

Custom Search

Home » Pharmacology » Pharmacology and drugs » Drug, pharmacology and therapeutic » Passage of drugs across membranes

Index Previous Next Your turn

Drug, pharmacology
and therapeutic
Passage of drugs across membranes User session
Methods for Register
studying drugs
Steps in drug
Before studying the passage of drugs across membranes it is necessary to recall the Login
discovery and composition and structure of the membrane. Bookmark, share this page
development
General
characteristics of the
Composition and structure of membranes
effects of drugs
Mechanism of action Plasma membrane which surrounds each cell consists of approximately 60% of
drugs on the phospholipids and 40% of protein.
molecular level
Pharmacokinetics
Definition of the Lipids
main
pharmacokinetic
parameters The lipids entering the composition of membranes are amphipathic, they consist of
Evolution of molecules containing a polar head and a non polar or hydrophobic tail. They are primarily:
plasma
concentrations of glycerophospholipids (substituted glycerol).
a drug after a sphingolipids (i.e. derived from sphingosine which is an alcohol substituted by a
single
administration fatty acid and a polar group). The sphingolipids are divided into three groups:
Evolution of sphingomyelins, cerebrosides and gangliosides.
plasma cholesterol consisting of a sterane nucleus substituted by a polar group (OH) and
concentrations of
a drug after a non polar flexible chain. Cholesterol, intercalated between other lipids,
repeated reinforces the membrane structure.
administrations
Passage of drugs These amphipathic lipids (glycerophospholipids and sphingolipids) are naturally
across oriented to form a bilayer: polar groups located on both sides and the non polar tails in the
membranes
Composition middle.
and structure of
membranes The fluidity of the bilayer depends on temperature, but also on its composition. The
Lipids unsaturated fatty acids which form less linear chains than the saturated fatty acids
Proteins
Transfer of increase membrane fluidity.
molecules and
drugs across Proteins
membranes
Transfer
through the The proteins found in membranes are either inserted in the lipid bilayer, inside or outside,
lipid bilayer: or transmembrane on both sides,.
passive
diffusion
Transfer
These proteins constitute:
through
membrane cell-surface receptors (generally glycoproteins, which ensure the intercellular
protein communications),
structures structures which ensure the exchange of ions and certain molecules between the
Direct active
transport by cell and its environment: pumps such as Na+ /K+-ATPase, channels,
pumps �exchangers�.
Indirect
active
transport Transfer of molecules and drugs across membranes
Transport by
exocytosis To penetrate into the cell, the drug must cross the cytoplasmic membrane. To pass from a
and
endocytosis
compartment to another, the drug must cross one or several membranes. The
Routes of drug membranes consist of cells bound to each other more or less tightly. These cells are
administration located on a basement membrane, itself more or less permeable to molecules. One
Drug distribution distinguishes:
from blood
Tissue distribution
of drugs 1. transcellular transfer
Biotransformations When the cells are tightly against each other, as in the endothelium of the cerebral
Elimination of capillaries, the drug must cross the cells themselves, i.e. the cytoplasmic
drugs
Pharmacokinetics
membrane, to pass from one compartment to the other.
and dosage of 2. paracellular transfer:
drugs When the epithelial cells are separated from each other by looser junctions, the

https://www.pharmacorama.com/en/Sections/Pharmacokinetics-4.php 1/4
6/2/2020 Passage of drugs across membranes - Pharmacorama
Advertisement molecules can pass through these junctions called �gap junctions�. The
paracellular transfer of a molecule depends primarily on its molecular weight and
its flexibility.
3. porous filter:
Certain epithelia, like that of the renal glomerulus, bear pores permeable to
molecules smaller than the pores. At the level of the renal glomerulus, the
molecules whose molecular weight is lower than 68 000 can theoretically pass,
but more the molecular weight of a molecule approaches 68 000, more its transfer
becomes difficult. Other parameters than the molecular weight (directly linked to
the size), such as charges or flexibility, are also to be taken into consideration.

Transfer through the lipid bilayer: passive diffusion

The transfer through a lipid bilayer is passive without requiring energy. The lipid bilayer
membrane constitutes a barrier:

impermeable to ions such as Na+, K+, Cl - , to polar molecules even non charged,
i.e. non-ionic, like glucose, and proteins.
permeable to non polar molecules (liposoluble or hydrophobic) of low or middle
molecular weight, and to molecules at the gas state and small molecules of low
polarity.

Passive diffusion through a lipid bilayer

The passage through the membrane is directed from the most concentrated solution
towards the least concentrated solution until obtaining an equilibrium. The rate of transfer
depends on the area S on the membrane, on the concentrations C1 and C2 on both sides
of the membrane and on a diffusion constant K linked to the liposolubility and the size of
the molecule (the smaller the molecule, the easier the transfer).

V = K.S. (C2 - C1)

The liposoluble character of a molecule is determined by the measurement of its partition

coefficient between an aqueous solvent and an organic solvent like hexane. The
liposoluble or non-polar molecules accumulate in organic solvent and the polar molecules
in water.

The polarity of a drug depends on its ionization and one distinguishes three categories:

1. Permanently ionized molecules, whatever the pH, for example those with a
quaternary ammonium. These molecules, in theory, do not cross the lipid bilayer
by passive diffusion.
2. Neutral molecules, not ionized, whatever the pH. It is the case of the organic
solvents which cross the lipid bilayer easily. This rule has limitations, in
particular concerning intestinal absorption because it takes place from an aqueous
medium. A very lipophilic molecule but almost insoluble in water can be poorly
absorbed. A low availability can be the consequence of a low solubility in water.
3. Molecules whose ionization depends on pH: in a neutral state, they cross the lipid
bilayer , but not in the ionized state. The acid drugs dissociate in a basic medium
and the bases in an acidic medium, to give ionized molecules. The pKa of an acid
is the pH at which it is 50% dissociated. For example, an acid drug R-COOH
partially dissociated in R-COO - + H + , neutral form R-COOH crosses
membranes but not the ionized form R-COO - .
https://www.pharmacorama.com/en/Sections/Pharmacokinetics-4.php 2/4
6/2/2020 Passage of drugs across membranes - Pharmacorama
Consequently, when two compartments at different pH are separated by a membrane, the
equilibrium of the concentrations of a drug R-COOH on both sides of the membrane will
be moved and drug R-COOH will accumulate in the basic compartment where it
dissociates.

Transmembrane transfer of an acid drug according to pH

Binding of the drugs to plasma proteins, in particular to albumin, which can go from 0% to
99% modifies their transfer through the membranes. In the free state, i.e. unbound to
plasma proteins, the liposoluble drugs, if there is a gradient of favorable concentration,
cross the lipid membrane, whereas the fraction bound to plasma or tissue proteins does
not cross it.

Transmembrane transfer of a drug according to its protein binding

Albumin is a protein with a molecular weight of 68000 daltons, present in plasma at a

concentration approximately 50 g/L. It is synthesized by the liver and degraded primarily
by the vascular endothelium. Its plasma half-life is approximately 20 days. In addition to
its role in oncotic pressure, it binds various endogenous molecules and drugs. There
are on a molecule of albumin six different types of sites with different affinities for drugs.

The equilibrium for a drug between the free fraction, D, and the bound fraction, DP, is
reversible and non-static in the body because the blood circulation causes dynamic
changes.

Blood cells, mainly red cells, can play a role comparable to that of albumin for drugs that
they bind or incorporate.

Transfer through membrane protein structures

The transfer through the protein structures of membranes is carried out by active
transport, i.e. using energy provided by cellular metabolism.

Direct active transport by pumps

The active transport requires energy, generally provided by ATP hydrolysis. The Na+/K+-
ATPASE pump, Mg2 + dependant, uses the energy of ATP to polarise the cell by
extruding three Na+ ions and incorporating two K+ ions, which creates a potential

https://www.pharmacorama.com/en/Sections/Pharmacokinetics-4.php 3/4
6/2/2020 Passage of drugs across membranes - Pharmacorama
difference between the intracellular medium and the extracellular medium. There are
other pumps: a Ca2+-ATPASE pump localized on the level of the cytoplasmic membrane
and at the level of the endoplasmic reticulum and an H+ /K+-ATPASE pump.

A particular membrane protein, P-glycoprotein, or P170 because its molecular weight is

170 Kd, uses, like the Na+/K+-ATPASE pump , the energy supplied by the hydrolysis of
ATP to drive certain drugs out of the cell. This glycoprotein, also called Multi drug
transporter, protects the cell against xenobiotics but, as it is expressed in the majority of
cancerous cells, it also expel antineoplastic drugs out of cancerous cells, thus explaining
their resistance to chemotherapy which is called MDR �Multi drug resistance�. Drugs
such as verapamil or quinidine inhibit P-glycoprotein but have other properties making
their use as inhibitors of P-glycoprotein difficult. P-glycoprotein present in the blood-brain
barrier reduces penetration of certain drugs into the brain. It can also reduce their
digestive absorption.

Various microorganisms have in their plasma membrane, in addition to P-glycoprotein,

proton-dependant pumps which drive toxic molecules out of their cytoplasm.

Indirect active transport

The energy necessary for facilitated diffusion, or secondary active transport, is supplied
by the ion gradients on both sides of the membrane. It is not carried out through the lipid
bilayer but through the protein structures.

It relates to only a small number of compounds:

1. molecules implicated in metabolism, like glucose, amino acids, certain

transmitters and drugs of close chemical structure. The energy necessary for their
transport can be supplied by the sodium gradient.
The kinetics of transfer is of Michaelis Menten type with maximum rate and
possibility of competition between molecules. When sodium and the substrate
cross the membrane in the same direction, the transport is called symport and
�antiport� when they cross in opposite directions.
2. peptides formed of 2 or 3 acids amino are partially absorbed by the digestive tract
and reabsorbed in the nephron by specific carriers using the H+ gradient as
source of energy. These carriers are involved in the digestive absorption of drugs
with a chemical peptidic-like structure such as beta-lactamines. A polypeptide
such as insulin can cross the blood-brain barrier but the responsible mechanisms
are poorly understood.
3. ions like Na+, K+, Ca2+, Cl _ , whose membrane transporters are channels and
exchangers:
channels whose opening and closure depend either on the
intra/extracellular potential difference (opening during depolarization), or
on the presence of receptors which can be activated or inhibited by
various transmitters
exchangers, Na+/Ca2+ for example.

Transport by exocytosis and endocytosis

Exocytosis consists of the exit out of the cell of molecules contained in vesicles which
fuse with the plasma membrane and release their contents outside. It is the mode of
release of transmitters.

Endocytosis consists of the absorption by a cell of an extracellular molecule. After its

inclusion in a vesicle formed by an invagination of the plasma membrane, the molecule
penetrates into the cytoplasm. It is, for example, the process used by hepatocytes to take
up lipoproteins and transferrin,.

Oligonucleotides of 10 to 20 units, such as those used in antisense therapy

(oligonucleotides complementary to the mRNA on which they bind) penetrate into cells by
various mechanisms but primarily by endocytosis. In fact, an oligonucleotide penetrates
better into cells that an isolated nucleotide.

Me gusta 0 Tweet Compartir 4

Previous Next

https://www.pharmacorama.com/en/Sections/Pharmacokinetics-4.php 4/4