Clinical Relevance of Hepatic and Renal P-gp/BCRP Inhibition of Drugs: An International Transporter Consortium Perspective.
Clinical Relevance of Hepatic and Renal P-gp/BCRP Inhibition of Drugs: An International Transporter Consortium Perspective.
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DOI：
10.1002/cpt.2670
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发表时间：
2022-09
影响因子：
6.7
通讯作者：
Zamek-Gliszczynski, Maciej
中科院分区：
文献类型：
--
作者：
Taskar, Kunal S.;Yang, Xinning;Neuhoff, Sibylle;Patel, Mitesh;Yoshida, Kenta;Paine, Mary F.;Brouwer, Kim L. R.;Chu, Xiaoyan;Sugiyama, Yuichi;Cook, Jack;Polli, Joseph W.;Hanna, Imad;Lai, Yurong;Zamek-Gliszczynski, Maciej
P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）在药物相互作用（DDI）和限制药物吸收以及限制具有某些理化性质的药物的脑渗透中的作用是众所周知的。据报告，肠道中药物对P-gp/BCRP的抑制可增加底物药物的全身暴露量。先前的国际转运蛋白联盟（ITC）观点讨论了血脑屏障中P-gp/BCRP抑制的可行性及其影响。本ITC观点具体阐述和讨论了药物对肝脏和肾脏P-gp/BCRP（称为全身性）的抑制作用，以及是否对底物药物处置产生任何影响。该观点总结了关于药物全身性P-gp和BCRP抑制的临床循证建议，重点关注胆汁和主动肾脏排泄途径。评估肝脏和肾脏中全身性P-gp和BCRP抑制的临床相关性的方法包括（1）治疗涉及静脉给药底物或抑制剂的DDI;（2）全身水平P-gp介导的DDI的体外至体内外推;和（3）治疗具有胆汁排泄和相关DDI贡献相关信息的药物。根据迄今为止报告的全部证据，该观点支持肝脏或肾脏中P-gp或BCRP抑制的临床DDI风险有限。
The role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in drug-drug interactions (DDIs) and limiting drug absorption as well as restricting the brain penetration of drugs with certain physicochemical properties is well known. P-gp/BCRP inhibition by drugs in the gut has been reported to increase the systemic exposure to substrate drugs. A previous International Transporter Consortium (ITC) perspective discussed the feasibility of P-gp/BCRP inhibition at the blood-brain barrier and its implications. This ITC perspective elaborates and discusses specifically the hepatic and renal P-gp/BCRP (referred as systemic) inhibition of drugs and whether there is any consequence for substrate drug disposition. This perspective summarizes the clinical evidence-based recommendations regarding systemic P-gp and BCRP inhibition of drugs with a focus on biliary and active renal excretion pathways. Approaches to assess the clinical relevance of systemic P-gp and BCRP inhibition in liver and kidney included (1) curation of DDIs involving intravenously administered substrates or inhibitors; (2) in vitro-to-in vivo extrapolation of P-gp- mediated DDIs at the systemic level; and (3) curation of drugs with information available about the contribution of biliary excretion and related DDIs. Based on the totality of evidence reported to date, this perspective supports limited clinical DDI risk upon P-gp or BCRP inhibition in liver or kidney.
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