Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070, Basel, Switzerland.
Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland.
AAPS J. 2020 Oct 8;22(6):128. doi: 10.1208/s12248-020-00513-5.
Physiologically based pharmacokinetic (PBPK) modeling is less well established for substrates of UDP-glucuronosyltransferases (UGT) than for cytochrome P450 (CYP) metabolized drugs and more verification of simulations is necessary to increase confidence. To address specific challenges of UGT substrates, we developed PBPK models for four drugs cleared majorly via glucuronidation (lorazepam, oxazepam, naloxone, and zidovudine). In vitro to in vivo scaling of intrinsic clearance generated with co-cultured human hepatocytes was applied for hepatic metabolism and extra-hepatic clearance was extrapolated based on relative expression of UGT isoforms in the liver, kidney, and intestine. Non-metabolic clearance and the contributions of individual UGT isoforms to glucuronidation were based on in vitro and in vivo studies taken from the literature and simulations were verified and evaluated with a broad set of clinical pharmacokinetic data. Model evaluation showed systemic clearance predictions within 1.5-fold for all drugs and all simulated parameters were within 2-fold of observed. However, during the verification step, top-down model fitting was necessary to adjust for under-prediction of zidovudine V and renal clearance and over estimation of intestinal first pass for lorazepam, oxazepam, and zidovudine. The impact of UGT2B15 polymorphisms on the pharmacokinetics of oxazepam and lorazepam was simulated and glucuronide metabolites were also simulated for all four drugs. To increase confidence in predicting extra-hepatic clearance, improvement of enzyme phenotyping for UGT substrates and more quantitative tissue expression levels of UGT enzymes are both needed. Prediction of glucuronide disposition is also challenging when active transport processes play a major role.
生理药代动力学（PBPK）模型在尿苷二磷酸葡萄糖醛酸转移酶（UGT）底物方面的建立不如细胞色素 P450（CYP）代谢药物完善，需要更多的模拟验证来提高可信度。为了解决 UGT 底物的具体挑战，我们为主要通过葡萄糖醛酸化清除的四种药物（劳拉西泮、奥沙西泮、纳洛酮和齐多夫定）开发了 PBPK 模型。应用共培养人肝细胞产生的内在清除率的体外到体内比例法进行肝内代谢，根据肝、肾和肠中 UGT 同工型的相对表达来推断肝外清除率。非代谢清除率和各个 UGT 同工型对葡萄糖醛酸化的贡献基于来自文献的体外和体内研究，模拟结果通过广泛的临床药代动力学数据进行了验证和评估。模型评估显示，所有药物的全身清除率预测值都在 1.5 倍以内，所有模拟参数与观察值的比值都在 2 倍以内。然而，在验证步骤中，需要进行自上而下的模型拟合来调整齐多夫定 V 和肾清除率的预测不足以及劳拉西泮、奥沙西泮和齐多夫定的肠首过效应的高估。还模拟了 UGT2B15 多态性对奥沙西泮和劳拉西泮药代动力学的影响，并为所有四种药物模拟了葡萄糖醛酸化物代谢物。为了提高预测肝外清除率的可信度，需要改进 UGT 底物的酶表型和 UGT 酶的更定量组织表达水平。当主动转运过程起主要作用时，预测葡萄糖醛酸化物的处置也具有挑战性。
