Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
Drug Metabolism, Gilead Sciences Inc., Foster City, California, USA.
CPT Pharmacometrics Syst Pharmacol. 2024 Jan;13(1):118-131. doi: 10.1002/psp4.13062. Epub 2023 Oct 20.
Hepatic impairment (HI) moderately (<5-fold) affects the systemic exposure (i.e., area under the plasma concentration-time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine. However, the effect of HI on their AUC is much greater (>10-fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) over the sum of metabolic and biliary CLs as important in predicting the impact of HI on the AUC of dual OATP/CYP3A substrates. Because HI may reduce hepatic CYP3A-mediated CL to a greater extent than biliary efflux CL, the greater the contribution of the former versus the latter, the greater the impact of HI on drug AUC ratio (AUCR ). Using physiologically-based pharmacokinetic modeling and simulation, we predicted relatively well the AUCR of OATP substrates that are not significantly metabolized (pitavastatin, rosuvastatin, valsartan, and gadoxetic acid). However, there was a trend toward underprediction of the AUCR of the dual OATP/CYP3A4 substrates fimasartan and atorvastatin. These predictions improved when the sinusoidal efflux CL of these two drugs was increased in healthy volunteers (i.e., before incorporating the effect of HI), and by modifying the directionality of its modulation by HI (i.e., increase or decrease). To accurately predict the effect of HI on AUC of hepatobiliary cleared drugs it is important to accurately predict all hepatobiliary pathways, including sinusoidal efflux CL.
肝脏损伤（HI）会适度（<5 倍）影响经肝窦有机阴离子转运多肽（OATP）转运体作为底物且以原形经胆汁和/或尿液排泄的药物的全身暴露（即，血浆浓度-时间曲线下面积 [AUC]）。然而，对于也是细胞色素 P450（CYP）3A 酶底物的药物，HI 对其 AUC 的影响要大得多（>10 倍）。通过扩展清除模型，我们通过模拟发现，窦状隙流出清除率（CL）与代谢和胆汁 CL 总和的比值对于预测 HI 对双重 OATP/CYP3A 底物 AUC 的影响很重要。由于 HI 可能会比胆汁流出 CL 更大程度地降低肝 CYP3A 介导的 CL，前者相对于后者的贡献越大，HI 对药物 AUC 比值（AUCR）的影响就越大。通过生理相关的药代动力学建模和模拟，我们很好地预测了经代谢作用不明显的 OATP 底物的 AUCR（培伐他汀、瑞舒伐他汀、缬沙坦和钆塞酸）。然而，对于双重 OATP/CYP3A4 底物非那沙坦和阿托伐他汀，AUCR 的预测存在一定的趋势。当健康志愿者增加这两种药物的窦状隙流出 CL（即，在纳入 HI 影响之前）时，以及通过改变其被 HI 调节的方向（即增加或减少）时，这些预测得到了改善。要准确预测 HI 对肝胆清除药物 AUC 的影响，重要的是要准确预测所有肝胆途径，包括窦状隙流出 CL。
