The mechanism of absorption for drugs or the transport of drugs across membranes entails one or more of the following processes:
- Passive diffusion: This is the most common mode of drug transport across cell membranes and it is governed by a concentration gradient across a membrane, which makes a drug move from an area of high concentration to one of low concentration. The rate of diffusion depends mainly on the lipid–water partition coefficient rather than on lipid solubility per se.
- Active transport: This is an energy-dependent movement of compounds across membranes, most often against their concentration gradient. In general, drugs will not be actively transported unless they sufficiently resemble the endogenous substances (such as sugars, amino acids, nucleic acid precursors) that are the normal substrates for the particular carrier system. This transport involves the reversible binding of the molecule to be transferred to a membrane component (a carrier) of complementary configuration.
- Transport by special carrier protein or Facilitated diffusion:The transfer of drugs by facilitated diffusion has many of the characteristics associated with active transport, including being a protein carrier-mediated transport system that shows saturability and selectivity. It differs from active transport, however, in that no energy input is required beyond that necessary to maintain normal cellular function. In facilitated transport the movement of the transported molecule is from regions of higher to regions of lower concentrations, so the driving force for facilitated transport is the concentration gradient. Although the initial rate of drug transfer will be proportional to the magnitude of the concentration gradient, at some point further increases in drug concentration no longer increase the transport rate; that is, Tm has been reached, since the binding sites on the carrier are now completely saturated.
- Filtration: The rate of filtration depends both on the existence of a pressure gradient as a driving force and on the size of the compound relative to the size of the pore through which it is to be filtered. In biological systems, the passage of many small water-soluble solutes through aqueous channels in the membrane is accomplished by filtration. The hypothetical diameter of these pores is about 7 Å, a size that generally limits passage to compounds of molecular weight less than 100 (e.g., urea, ethylene glycol).
- Bulk flow: Most substances, lipid-soluble or not, cross the capillary wall at rates that are extremely rapid in comparison with their rates of passage across other body membranes. In fact, the supply of most drugs to the various tissues is limited by blood flow rather than by restraint imposed by the capillary wall. This bulk flow of liquid occurs through intercellular pores and is the major mechanism of passage of drugs across most capillary endothelial membranes, with the exception of those in the CNS.
- Ion pair transport: Absorption of some highly ionized compounds like sulfonic acids and quaternary ammonium compounds from the gastrointestinal tract cannot be explained in terms of the transport mechanisms discussed earlier. These compounds are known to penetrate the lipid membrane despite their low lipid–water partition coefficients. It is postulated that these highly lipophobic drugs combine reversibly with such endogenous compounds as mucin in the gastrointestinal lumen, forming neutral ion-pair complexes; it is this neutral complex that penetrates the lipid membrane by passive diffusion.
- Endocytosis: Endocytosis involves the cellular uptake of exogenous molecules or complexes inside plasma membrane-derived vesicles. This process can be divided into two major categories: (1) adsorptive or phagocytic uptake of particles that have been bound to the membrane surface and (2) fluid or pinocytotic uptake, in which the particle enters the cell as part of the fluid phase. The solute within the vesicle is released intracellularly, possibly through lysosomal digestion of the vesicle membrane or by intermembrane fusion.