Role of P-glycoprotein in the hepatic metabolism of tacrolimus
Role of P-glycoprotein in the hepatic metabolism of tacrolimus
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DOI：
10.1080/00498250500485115
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发表时间：
2006-01-01
期刊：
影响因子：
1.8
通讯作者：
Chiou, WL
中科院分区：
文献类型：
--
作者：
Jeong, H;Chiou, WL
主要目的是确定P-糖蛋白(P-gp)对他克莫司(P-gp和细胞色素P450(CYP)3A4底物)肝脏代谢的潜在影响，并探讨P-gp和细胞色素P450(CYP)3A4相互作用的各种可能因素。采用大鼠肝脏离体灌流系统，研究了他克莫司在P-gp抑制剂GF120918存在下的肝组织分布，并进行了全面的药动学分析。GF120918显著降低了平均内源性代谢清除量(基于充分搅拌和管状模型，分别降低了86%和41%)以及肝脏清除量(从47.3至44.2mlmin(-1))。可能有助于这些观察的潜在因素，如GF120918对肝脏代谢的影响或对他克莫司分布的影响，被调查并发现可以忽略不计。综上所述，GF120918抑制P-gp可降低其底物药物对肝脏的清除，但其机制尚不清楚。
The main objective was to determine the potential effect of P-glycoprotein (P-gp) modulation on hepatic metabolism of tacrolimus, a P-gp and cytochrome P450(CYP) 3A4 substrate, and to investigate various potential factors that may contribute to the interaction between P-gp and CYP. An isolated perfused rat liver system was used to study the hepatic disposition of tacrolimus in the presence of a P-gp inhibitor, GF120918, and a comprehensive pharmacokinetic analysis was conducted. GF120918 significantly decreased mean intrinsic metabolic clearance ( by 86 and 41% based on the well-stirred and tube models, respectively) as well as hepatic clearance ( from 47.3 to 44.2 ml min(-1)). Potential factors that might contribute to these observations, such as the effects of GF120918 on hepatic metabolism or on distribution of tacrolimus, were investigated and found to be negligible. In conclusion, it was shown that P-gp inhibition by GF120918 reduces hepatic clearances of its substrate drugs although the mechanism is yet to be determined.