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Species differences in the hepatobiliary disposition of morphine-6-glucuronide mediated by hepatic transporters in rats and humans

文献类型：期刊论文

作者Guo, Zi-tao1,2; Wang, Hong2; Xie, Ning-jie2,3; Zhou, Yu-fan2,3; Zhang, Meng-lin2,3; Kang, Xin-yao2,3; Wang, Jue2; Zhu, Qing2; Chen, Xiao-yan1,2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-09-15
页码12
关键词morphine-6-glucuronide HOATPs/rOatps HMRP2/rMrp2 hepatobiliary disposition enterohepatic circulation species difference
ISSN号1671-4083
DOI10.1038/s41401-025-01658-9
英文摘要Morphine-6-glucuronide (M6G), the active metabolite of morphine, is currently in clinical development due to its higher analgesic activity. In humans, intravenously administered M6G was predominantly eliminated unchanged through the kidney, whereas it was excreted into the urine as parent drug as well as its metabolites morphine and M3G in normal rats. In bile-duct-cannulated rats, however, bile excretion of the parent drug was the main route of clearance. In the study, we investigated the mechanisms underlying the species differences in vivo disposition of M6G. In hepatocyte uptake assay, we showed that M6G uptake in rat hepatocytes was 75-fold higher than that in human hepatocytes. Hepatic uptake transporter phenotyping study identified M6G as a substrate for rat rOatplal, rOatpla4, rOatp1b2, as well as for human hOATP1B1 and hOATP1B3. Among these, rOatps exhibited significantly stronger uptake of M6G compared to hOATPs. Furthermore, M6G was not a substrate for the canalicular efflux transporters MDR1, hBCRP/rBcrp, hBSEP/rBsep, and hMRP2, but it was recognized by rMrp2. These findings aligned with the observation that M6G exhibited significant biliary excretion in the rat sandwich cultured hepatocyte (SCH) model, but not in the human SCH. Additionally, no species differences were observed in renal uptake mediated by OAT3. Overall, M6G underwent renal clearance in humans via glomerular filtration and active secretion primarily mediated by hOAT3. Although a portion of M6G was also eliminated through the kidney in rats, the majority was subjected to enterohepatic circulation mediated primarily by rOatps and rMrp2, leading to the formation of morphine and M3G, which were subsequently excreted in the urine. The marked difference in the uptake activities of sinusoidal transporters hOATPs/rOatps and the substrate specificity of canalicular transporters hMRP2/rMrp2 were critical factors underlying the species differences in the hepatobiliary disposition of M6G.
WOS关键词INTERINDIVIDUAL VARIABILITY ; MORPHINE PHARMACOKINETICS ; RELATIVE CONTRIBUTION ; BILIARY CLEARANCE ; ACTIVE-TRANSPORT ; DRUG-METABOLISM ; EXPRESSION ; EXCRETION ; MONKEY ; DOG
资助项目National Natural Science Foundation of China[82373939] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001571206100001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/321441]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Chen, Xiao-yan
作者单位1.Shanghai Univ, Sch Environm & Chem Engn, Shanghai 200444, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Zi-tao,Wang, Hong,Xie, Ning-jie,et al. Species differences in the hepatobiliary disposition of morphine-6-glucuronide mediated by hepatic transporters in rats and humans[J]. ACTA PHARMACOLOGICA SINICA,2025:12.
APA Guo, Zi-tao.,Wang, Hong.,Xie, Ning-jie.,Zhou, Yu-fan.,Zhang, Meng-lin.,...&Chen, Xiao-yan.(2025).Species differences in the hepatobiliary disposition of morphine-6-glucuronide mediated by hepatic transporters in rats and humans.ACTA PHARMACOLOGICA SINICA,12.
MLA Guo, Zi-tao,et al."Species differences in the hepatobiliary disposition of morphine-6-glucuronide mediated by hepatic transporters in rats and humans".ACTA PHARMACOLOGICA SINICA (2025):12.

入库方式： OAI收割

来源：上海药物研究所

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