Drug absorption mechanisms

It is well established today that drug absorption through the alimentary canal walls is a complex event, which involves, in many cases, parallel or sequent microprocesses at the apical membrane of the absorptive cell (enterocyte) or between them (paracellular absorption). In addition to the various types of diffusion processes across the enterocyte membrane, numerous specific proteins—transporters and efflux pumps—are involved in the intricate drug absorption process. In the following sections the various epithelial tissues of the different organs of the GI tract will be looked at briefly. A review of major drug absorption mechanisms across epithelial cells, as they are customary today will follow. 

Apart from the predominant lymphatic drug absorption mechanism, other possible mechanisms of drug transport through intestinal barriers include transcellular and paracellular absorption of drug molecules, inhibition of P-gp and/or CYP450 to accumulate the intracellular drug concentration, and production of lipoprotein/ chylomicron. 

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

It is far more difficult to establish the mechanism(s) of drug absorption in humans. Most investigators analyze drug absorption data in humans (from blood or urine data) by assuming first-order absorption kinetics. For the most part this assumption seems quite... 

There are circumstances, however, where blood flow to the GIT may influence drug absorption. Those compounds absorbed by active or specialized mechanisms require membrane participation in transport, which in turn depends on the expenditure of metabolic energy by intestinal cells. If blood flow and therefore oxygen delivery is reduced, there may be a reduction in... 

WN Charman, CJH Porter, S Mithani, JB Dressman. Physicochemical and physiological mechanisms for the effects of food on drug absorption the role of lipids and pH. J Pharm Sci 86 269-282, 1997. 

In conclusion, it should be apparent from this discussion of the absorption mechanisms that, although the major features influencing drug absorption are well known, implementation of a coherent delivery strategy is highly specific for any compound, and many variables need to be adjusted for their significant influence on absorption and more importantly, on bioavailability. In addition, from the suggestion of the role of... 

The first purified and characterized drug substances were administered as aerosols as a topical treatment for asthma approximately 50 years ago. More recently, drugs have been evaluated for systemic delivery. For each category of drug the mechanism of clearance from the airways must be considered. These mechanisms may be listed as mucociliary transport, absorption, and cell-mediated translocation. The composition and residence time of the particle will influence the mechanism of clearance. 

Percutaneous Absorption Drugs-Cosmetics-Mechanisms-Metho-dology, Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and Howard I. Maibach... 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

The most commonly used methods for studies of partitioning into a membrane, mechanisms of drug absorption, and interactions with epithelial proteins, such as transporters and enzymes, are the cell culture-based models. These are both sim-... 

Solvents used to increase solubility for compounds during screening of permeability across the cell monolayers, together with commonly used excipients for formulations, can also affect the barrier as they contain ingredients which enhance drug absorption [100, 151]. There are different mechanisms by which these compounds can modulate the barrier [4, 149, 150] for example, they may increase the tight junctional pathway inhibiting carrier-mediated transport, or cholesterol... 

Muranishi, S., Yamamoto, A., Mechanisms of absorption enhancement through gastrointestinal epithelium, in Drug Absorption Enhancement, de Boer, A. G. (ed.), Harwood Academic Publishers, 1994, 67-100. 

It is important to recognize that the in vitro permeability obtained in cell mono-layers (such as Caco-2 models) should be considered as a qualitative rather than quantitative value. Especially poor are predictions of fraction dose absorbed for carrier-mediated drugs with low Caco-2 permeability and predictions of high fraction dose absorbed in humans [7, 20, 42, 48, 51]. However, it is possible to establish a reasonably good IVIVC correlation when passive diffusion is the dominating absorption mechanism. 

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