Role of transport proteins in drug absorption, distribution and excretion

作者：Andrew D. Ayrton, Paul M. Morgan · 发表于：Xenobiotica · 年份：2001 · DOI：10.1080/00498250110060969 · 被引用次数：426 · 研究领域：Drug Transport and Resistance Mechanisms、Pharmacological Effects and Toxicity Studies、Cannabis and Cannabinoid Research

1. The molecular and functional characterization of transport proteins is emerging rapidly and significant numbers of drugs have been shown to be substrates or inhibitors. The purpose of this review is to highlight the in vivo preclinical and clinical evidence that supports a role for transport proteins in attenuating the absorption, distribution and excretion (ADE) of drugs. 2. For absorption, a clear role has emerged for P-glycoprotein in limiting permeability across the gastrointestinal tract. As a result, a wide variety of drugs suffer from incomplete, variable and non-linear absorption. Similarly, at the blood-brain barrier a range of drugs has limited brain penetration due to P-glycoprotein-mediated efflux, which can limit therapeutic effectiveness of CNS agents. In the liver, transport proteins are present on the sinusoidal membrane that can be the rate-limiting step in hepatic clearance for some drugs. Mechanistic studies clearly suggest a key role and broad substrate specificity for the OATP family of sinusoidal transporters. Mainly ATP-dependent transport proteins such as P-glycoprotein and MRP2 govern active biliary excretion. 3. Drug-drug interactions have been demonstrated involving inhibition or induction of transport proteins. Clinically significant interactions in the gastrointestinal tract and kidney have been observed with inhibitors such as ketoconazole, erythromycin, verapamil, quinidine, probenecid and cimetidine. Clinically significant inhibition at the ...