Abstract：
Hepatic impairment, due to liver cirrhosis, decreases the activity of cytochrome P450 enzymes (CYPs). The use of physiologically based pharmacokinetic (PBPK) modeling to predict this effect for CYP substrates has been well-established, but the effect of cirrhosis on uridine-glucuronosyltransferase (UGT) activities is less studied and few PBPK models have been reported. UGT enzymes are involved in primary N-glucuronidation of midazolam and glucuronidation of 1\'-OH-midazolam following CYP3A hydroxylation. In this study, Simcyp was used to establish PBPK models for midazolam, its primary metabolites midazolam-N-glucuronide (UGT1A4) and 1\'-OH midazolam (CYP3A4/3A5), and the secondary metabolite 1\'-OH-midazolam-O-glucuronide (UGT2B7/2B4), allowing to simulate the impact of liver cirrhosis on the primary and secondary glucuronidation of midazolam. The model was verified in noncirrhotic subjects before extrapolation to cirrhotic patients of Child-Pugh (CP) classes A, B, and C. Our model successfully predicted the exposures of midazolam and its metabolites in noncirrhotic and cirrhotic patients, with 86% of observed plasma concentrations within 5th-95th percentiles of predictions and observed geometrical mean of area under the plasma concentration curve between 0 hours to infinity and maximal plasma concentration within 0.7- to 1.43-fold of predictions. The simulated metabolic ratio defined as the ratio of the glucuronide metabolite AUC over the parent compound AUC (AUCglucuronide/AUCparent, metabolic ratio [MR]), was calculated for midazolam-N-glucuronide to midazolam (indicative of UGT1A4 activity) and decreased by 40% (CP A), 48% (CP B), and 75% (CP C). For 1\'-OH-midazolam-O-glucuronide to 1\'-OH-midazolam, the MR (indicative of UGT2B7/2B4 activity) dropped by 35% (CP A), 51% (CP B), and 64% (CP C). These predicted MRs were corroborated by the observed data. This work thus increases confidence in Simcyp predictions of the effect of liver cirrhosis on the pharmacokinetics of UGT1A4 and UGT2B7/UGT2B4 substrates. SIGNIFICANCE STATEMENT: This article presents a physiologically based pharmacokinetic model for midazolam and its metabolites and verifies the accurate simulation of pharmacokinetic profiles when using the Simcyp hepatic impairment population models. Exposure changes of midazolam-N-glucuronide and 1\'-OH-midazolam-O-glucuronide reflect the impact of decreases in UGT1A4 and UGT2B7/2B4 glucuronidation activity in cirrhotic patients. The approach used in this study may be extended to verify the modeling of other uridine glucuronosyltransferase enzymes affected by liver cirrhosis.
摘要：
肝功能损害，由于肝硬化,降低细胞色素P450酶（CYPs）的活性。使用基于生理的药代动力学（PBPK）模型来预测CYP底物的这种作用已经得到了完善。但肝硬化对尿苷-葡萄糖醛酸基转移酶（UGT）活性的影响研究较少，PBPK模型报道较少。UGT酶参与CYP3A羟基化后咪达唑仑的初级N-葡糖醛酸化和1'-OH-咪达唑仑的葡糖醛酸化。在这项研究中，Simcyp®用于建立咪达唑仑的PBPK模型，其主要代谢产物咪达唑仑-N-葡糖苷酸（UGT1A4）和1'-OH咪达唑仑（CYP3A4/3A5）和次级代谢产物1'-OH-咪达唑仑-O-葡糖苷酸（UGT2B7/2B4），允许模拟肝硬化对咪达唑仑的原发性和继发性葡萄糖醛酸化的影响。在外推到Child-Pugh（CP）A类肝硬化患者之前，在非肝硬化受试者中验证了该模型，B,和C.我们的模型成功地预测了咪达唑仑及其代谢物在非肝硬化和肝硬化患者中的暴露，86％的观察到的血浆浓度在预测的第5-95百分位数之内，并且观察到的AUCinf和Cmax的几何平均值在预测的0.7-1.43倍之内。模拟代谢率(AUC葡糖醛酸/AUCparent，MR),计算咪达唑仑-N-葡糖苷酸对咪达唑仑的影响（表明UGT1A4活性），并降低了40％（CPA），48%（CPB），和75%（CPC）。对于1'-OH-咪达唑仑-O-葡糖苷酸至1'-OH-咪达唑仑，MR（表明UGT2B7/2B4活性）下降了35％（CPA），51%（CPB），和64%（CPC）。观察到的数据证实了这些预测的MR。因此，这项工作增加了Simcyp®预测肝硬化对UGT1A4和UGT2B7/UGT2B4底物药代动力学影响的信心。意义陈述本文介绍了咪达唑仑及其代谢物的PBPK模型，并验证了使用Simcyp®肝功能损害人群模型时对药代动力学曲线的准确模拟。咪达唑仑-N-葡糖苷酸和1'-OH-咪达唑仑-O-葡糖苷酸的暴露变化反映了肝硬化患者UGT1A4和UGT2B7/2B4葡糖苷酸活性降低的影响。本研究中使用的方法可以扩展到验证受肝硬化影响的其他UGT酶的建模。
