Proteins
The proteins found in membranes are either inserted in the lipid bilayer, inside or outside, or transmembrane on both sides,.
These proteins constitute:
cell-surface receptors (generally glycoproteins, which ensure the intercellular communications),
structures which ensure the exchange of ions and certain molecules between the cell and its environment: pumps such as Na+ /K+-ATPase, channels, “exchangers”.
Transfer of molecules and drugs across membranes
To penetrate into the cell, the drug must cross the cytoplasmic membrane. To pass from a compartment to another, the drug must cross one or several membranes. The membranes consist of cells bound to each other more or less tightly. These cells are located on a basement membrane, itself more or less permeable to molecules. One distinguishes:
transcellular transfer When the cells are tightly against each other, as in the endothelium of the cerebral capillaries, the drug must cross the cells themselves, i.e. the cytoplasmic membrane, to pass from one compartment to the other.
paracellular transfer: When the epithelial cells are separated from each other by looser junctions, the molecules can pass through these junctions called “gap junctions”. The paracellular transfer of a molecule depends primarily on its molecular weight and its flexibility.
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:
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.
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.
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 - .
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.
