Suzuki Eiko, Koyama Kumiko, Nakai Daisuke, Goda Ryoya, Kuga Hiroshi, Chiba Kan
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-Ku, Tokyo, 140-8710, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Eur J Drug Metab Pharmacokinet. 2017 Dec;42(6):965-972. doi: 10.1007/s13318-017-0413-2.
Human in vitro and dog in vitro/in vivo researches indicate that the drug-drug interaction (DDI) of decreased plasma valproic acid (VPA) concentration by co-administration of carbapenem antibiotics is caused by inhibition of acylpeptide hydrolase (APEH)-mediated VPA acylglucuronide (VPA-G) hydrolysis by carbapenems. In this study, we investigated VPA disposition and APEH activities in TK-NOG chimeric mice, whose livers were highly replaced with human hepatocytes, to evaluate the utility of this animal model and the clinical relevance of the DDI mechanism.
VPA and VPA-G concentrations in plasma, urinary excretion of VPA-G and APEH activity in humanized livers were measured after co-administration of VPA with meropenem (MEPM) to chimeric mice.
After co-administration with MEPM to the chimeric mice, plasma VPA concentration more rapidly decreased than without the co-administration. An increase in plasma AUC and urinary excretion of VPA-G was also observed. APEH activity in humanized livers was strongly inhibited even at 24 h after co-administration of MEPM to the chimeric mice.
The DDI of VPA with carbapenems was successfully observed in chimeric mice with humanized livers. The DDI was caused by long-lasting inhibition of hepatic APEH-mediated VPA-G hydrolysis by carbapenems, which strongly supports the APEH-mediated mechanism of the clinical DDI. This is the first example showing the usefulness of chimeric mice with humanized livers for evaluation of a DDI via non-cytochrome P450 enzyme.
人体体外及犬类体外/体内研究表明，碳青霉烯类抗生素联合使用导致血浆丙戊酸（VPA）浓度降低的药物相互作用（DDI）是由碳青霉烯类抑制酰肽水解酶（APEH）介导的VPA酰基葡萄糖醛酸（VPA-G）水解所致。在本研究中，我们调查了肝脏高度被人肝细胞替代的TK-NOG嵌合小鼠体内VPA的处置情况及APEH活性，以评估该动物模型的实用性以及DDI机制的临床相关性。
向嵌合小鼠联合给予VPA和美罗培南（MEPM）后，测定血浆中VPA和VPA-G的浓度、VPA-G的尿排泄量以及人源化肝脏中的APEH活性。
嵌合小鼠联合给予MEPM后，血浆VPA浓度比未联合给药时下降得更快。还观察到血浆AUC增加以及VPA-G的尿排泄增加。在嵌合小鼠联合给予MEPM后24小时，人源化肝脏中的APEH活性仍受到强烈抑制。
在肝脏人源化的嵌合小鼠中成功观察到VPA与碳青霉烯类的DDI。该DDI是由碳青霉烯类对肝脏APEH介导的VPA-G水解的持久抑制引起的，这有力地支持了临床DDI的APEH介导机制。这是首个表明肝脏人源化的嵌合小鼠可用于评估经由非细胞色素P450酶的DDI的实例。
