Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption

Oral bioavailability requires absorption of drugs across the intestinal epithelium. This may be mediated by either the paracellular and/or transcellular routes. Passive transcellular absorption requires the appropriate physicochemical properties to allow permeation across the apical and basolateral membrane domains. Compounds demonstrating these properties are more likely to be recognised as substrates for intracellular metabolism, such as by cytochrome P450 isozymes, and/or secretory drug efflux systems, including P-glycoprotein, such that oral bioavailability will be limited. P-glycoprotein, which leads to multidrug resistance in tumour cells, is an ATP-dependent secretory drug efflux pump, encoded by the MDR1 gene in humans. It acts to clear the membrane lipid bilayer of lipophilic drugs, in the manner of a flippase. In the intestine, as well as at specific other epithelial and endothelial sites, P-glycoprotein expression is localised to the apical membrane, consistent with secretory detoxifying and absorption limitation functions. Other secretory efflux systems, such as multidrug-resistance associated protein (a glutathione S-conjugate transporter), fluorochrome efflux systems and the methotrexate efflux system, together with drug ionic charge and the intestinal pH microclimate, may mediate intestinal secretion of a wide variety of drugs. Direct evidence for P-glycoprotein limiting drug absorption comes from studies in vitro with human Caco-2 cells and includes non-linear dependence of absorption on substrate (vinblastine) concentration, increased absorption upon saturation of secretion and increased absorption upon inhibition of P-glycoprotein function, with modulators such as verapamil. P-glycoprotein-like mechanisms are implicated in the intestinal secretion of a variety of drugs, in addition to classical P-glycoprotein substrates, including cyclosporin, certain peptides, digoxin, fluoroquinolones, ranitidine and β-adrenoceptor antagonists. These drug interactions with P-glycoprotein may explain the pharmacokinetics of absorption in vivo. P-glycoprotein function may be integrated with drug metabolism, with several drugs being common substrates for P-glycoprotein and cytochrome P-450 3A. Recognising the interactions of drugs with intestinal secretory and metabolic systems that limit absorption will lead to novel strategies of overcoming problems of poor oral bioavailability.