Intestinal Absorption of Drugs Mediated by Drug Transporters: Mechanisms and Regulation

Abstract

The absorption of drugs from the gastrointestinal tract is one of the important determinants for oral bioavailability. Development of in vitro experimental techniques such as isolated membrane vesicles and cell culture systems has allowed us to elucidate the transport mechanisms of various drugs across the plasma membrane. Recent introduction of molecular biological techniques resulted in the successful identification of drug transporters responsible for the intestinal absorption of a wide variety of drugs. Each transporter exhibits its own substrate specificity, though it usually shows broad substrate specificity. In this review, we first summarize the recent advances in the characterization of drug transporters in the small intestine, classified into peptide transporters, organic cation transporters and organic anion transporters. In particular, peptide transporter (PEPT1) is the best-characterized drug transporter in the small intestine, and therefore its utilization to improve the oral absorption of poorly absorbed drugs is briefly described. In addition, regulation of the activity and expression levels of drug transporters seems to be an important aspect, because alterations in the functional characteristics and/or expression levels of drug transporters in the small intestine could be responsible for the intra- and interindividual variability of oral bioavailability of drugs. As an example, regulation of the activity and expression of PEPT1 is summarized.

Asymmetric Intestinal First-Pass Metabolism Causes Minimal Oral Bioavailability of Midazolam in Cynomolgus Monkey

“…As regards membrane transport in the small intestine, several transporters have been suggested to contribute to drug absorption Katsura and Inui, 2003;Daniel, 2004;Sai and Tsuji, 2004), and in particular, P-gp is involved in regulation of the intestinal permeation of various xenobiotics (Terao et al, 1996). Midazolam shows high membrane permeability and is categorized as BCS class I (Wu and Benet, 2005).…”

Bacampicillin Uptake Is Shared with Thiamine in Caco-2 Cells

“…20) It has also been suggested that diphenhydramine and procainamide share a common organic cation transporter. 7) As shown in Fig. 3, the finding that thiamine, but not diphenhydramine, exerted a significant trans-stimulatory effect on bacampicillin uptake in Caco-2 cells suggests that bacampicillin and thiamine share a common transport system on the Caco-2 cell membranes.…”

“…It is well known that a variety of organic cations are absorbed via specialized transport systems in the small intestine. 7,8) It is therefore possible that a kind of organic cation transporter is unexpectedly involved in the intestinal absorption of bacampicillin. Caco-2 cells express a large number of transporters with which to handle various endogenous and exogenous organic cations such as azasetron, 9) carnitine, 10,11) choline, 12) diphenhydramine, 13) guanidine, 14) 1-methyl-4-phenyl-pyridinium, 15) nicotine, 16) and thiamine.…”

Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

“…Thus, oral bioavailability is one of the key considerations for discovery and development of a new chemical entity (NCE). It is well recognized that poor oral bioavailability is one of the major causes of therapeutic variability, associated with the variable drug exposure (Beierle et al 1999;Bardelmeijer et al 2000;Katsura and Inui 2003). This is particularly important for drugs with narrow therapeutic window or potential for resistance development such as antibiotics and cytotoxic drugs (Bardelmeijer et al 2000).…”