Miyake Taiji, Fujita Yuito, Hirabayashi Manabu, Komiyama Natsuko, Morita Keiichi, Tachibana Tatsuhiko, Terao Kimio
Pharmaceutical Science Department, Translational Research Division, Chugai Pharmaceutical Co., Ltd., Yokohama-shi, Japan.
Pharmaceutical Science Department, Translational Research Division, Chugai Pharmaceutical Co., Ltd., Yokohama-shi, Japan.
Drug Metab Dispos. 2025 Apr;53(4):100050. doi: 10.1016/j.dmd.2025.100050. Epub 2025 Feb 10.
Drug clearance and drug-drug interactions are essential for pharmacokinetic assessment. However, current in vitro systems and animal scale-up approaches often fail to accurately predict drug disposition mediated by metabolizing enzymes, especially uridine diphosphate-glucuronosyltransferase (UGT). This study demonstrates how UGT-mediated drug disposition in humans can be predicted using hu-PXB mice (cDNA-uPA/severe combined immunodeficiency (SCID) mice transplanted with human-derived hepatocytes). To estimate human hepatic intrinsic clearance (CL) in vitro, UGT substrates (acetaminophen, entacapone, ketoprofen, lorazepam, oxazepam, posaconazole, and zidovudine) were incubated with cryopreserved human hepatocytes. CL was calculated based on the rate of substrate disappearance. In vivo human CL values were calculated based on literature. To evaluate human CL predictability, the 7 substrates were administered independently and intravenously to hu-PXB and SCID mice. We calculated the CL in the mice and compared it with that in humans. For predicting UGT-mediated drug-drug interactions, 2 UGT substrates were administered intravenously to hu-PXB mice with or without probenecid (a UGT inhibitor). We compared the changes in clearance with those in humans. The in vitro assay using hepatocytes significantly underpredicted CL in humans. Hu-PXB mice had a much better correlation with humans in CL (R = 0.95) compared with SCID mice (R = 0.69). Hu-PXB mice predicted the CL of UGT substrate drugs within 2-fold of the clinical values for every compound we evaluated. The decrease in clearance caused by probenecid in hu-PXB mice reflected that in humans. Our findings demonstrate that human drug disposition mediated by UGT can be predicted based on the in vivo studies using hu-PXB mice. SIGNIFICANCE STATEMENT: Human liver chimeric mice can accurately predict the clearance of uridine diphosphate-glucuronosyltransferase (UGT) substrate drugs and are likely to predict the magnitude of UGT-mediated drug-drug interactions. Findings from in vivo studies in humanized mice enable the selection of better candidates in drug discovery and allow for the more precise physiologically based pharmacokinetic modeling of UGT substrate drugs in clinical practice.
药物清除率和药物相互作用对于药代动力学评估至关重要。然而，当前的体外系统和动物放大方法往往无法准确预测由代谢酶介导的药物处置，尤其是尿苷二磷酸葡萄糖醛酸转移酶（UGT）。本研究展示了如何使用人源化肝脏小鼠（移植了人源肝细胞的cDNA-uPA/严重联合免疫缺陷（SCID）小鼠）来预测人体内UGT介导的药物处置。为了在体外估计人肝脏内在清除率（CL），将UGT底物（对乙酰氨基酚、恩他卡朋、酮洛芬、劳拉西泮、奥沙西泮、泊沙康唑和齐多夫定）与冻存的人肝细胞一起孵育。根据底物消失速率计算CL。体内人CL值根据文献计算。为了评估人CL的可预测性，将这7种底物分别静脉注射给人源化肝脏小鼠和SCID小鼠。我们计算了小鼠体内的CL，并将其与人体内的CL进行比较。为了预测UGT介导的药物相互作用，将2种UGT底物静脉注射给有或没有丙磺舒（一种UGT抑制剂）的人源化肝脏小鼠。我们将清除率的变化与人体内的变化进行了比较。使用肝细胞的体外试验显著低估了人体内的CL。与人源化肝脏小鼠相比，SCID小鼠在CL方面与人的相关性要差得多（人源化肝脏小鼠R = 0.95，SCID小鼠R = 0.69）。对于我们评估的每种化合物，人源化肝脏小鼠预测的UGT底物药物的CL在临床值的2倍以内。丙磺舒在人源化肝脏小鼠中引起的清除率降低反映了人体内的情况。我们的研究结果表明，基于使用人源化肝脏小鼠的体内研究可以预测UGT介导的人体药物处置。重要性声明：人肝脏嵌合小鼠可以准确预测尿苷二磷酸葡萄糖醛酸转移酶（UGT）底物药物的清除率，并可能预测UGT介导的药物相互作用的程度。在人源化小鼠体内研究的结果有助于在药物研发中选择更好的候选药物，并在临床实践中对UGT底物药物进行更精确的基于生理学的药代动力学建模。
