期刊
XENOBIOTICA
卷 31, 期 8-9, 页码 469-497出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/00498250110060969
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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 blood-brain barrier is more difficult to demonstrate, relying on pharmacodynamic and toxicodynamic changes, but an example is quinidine increasing loperamide-induced central effects in humans. 4. This review highlights the emerging role of transport proteins in ADE of drugs and suggests these need to be considered, in drug discovery and development, with respect to variability in drug disposition and response.
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