肠道CYP3A和P-gp:口服药物的吸收屏障

细胞色素P4 5 0 3A (CYP3A)亚族是人类药物代谢最重要的I相酶。由MDR1基因编码的外向转运载体蛋白P糖蛋白 (P gp)为药物外排泵。这两种蛋白质在口服药物吸收的主要部位胃肠道均有高表达 ,同时二者的底物具有明显的重叠性。近来 ,大量研究表明 ,决定口服药物生物利用度的主要因素是肠道细胞CYP3A对已吸收药物的生物转化作用和肠道细胞中P gp对已吸收药物的主动外排作用。如果药物为CYP3A和 (或 )P gp的底物 ,当其与CYP3A和P gp的抑制剂同时服用后 ,药物的口服生物利用度将可能升高

The intestinal cytochrome P450 3A and P-glycoprotein:barriers to drug absorption

Cytochrome P450 3A (CYP3A/CYP3A4), the major phase I drug metabolizing enzyme in humans, and the MDR1 gene expressed P-glycoprotein (P-gp), the drug efflux pump, are present at high levels in the villus tip of enterocytes of gastrointestinal tract, the primary site of absorption for orally administrated drugs, and share a significant overlap in substrate specificity. It has been recognized that metabolism by intestinal CYP3A/CYP3A4 is one of the major determinants of oral drug bioavailability. More recently, a large body of research has demonstrated that drug extrusion by intestinal P-gp can both reduce drug absorption and modulate the effects of inhibitors and inducers of CYP3A/CYP3A4-mediated metabolism. A growing number of animal data and clinical studies, both in vitro and in vivo, have indicated that concomitant administration of CYP3A/CYP3A4 inhibitors and/or P-gp inhibitors can increase the oral bioavailability of a wide range of drugs, which are CYP3A/CYP3A4 and P-glycoprotein substrates.