Valles B, Schiller C D, Coassolo P, De Sousa G, Wyss R, Jaeck D, Viger-Chougnet A, Rahmani R
Pharma Division, F. Hoffmann-La Roche, Basel, Switzerland.
Drug Metab Dispos. 1995 Oct;23(10):1051-7.
The arotinoid mofarotene is a novel potent anticancer compound. The metabolic profiles obtained from rat, dog, and human plasma showed a good correlation with the corresponding in vitro profiles observed with liver microsomes and hepatocytes. Interspecies differences in its metabolism were investigated using microsomes prepared from the livers of the mouse, rat, dog, cynomolgus monkey, and humans. These in vitro experiments showed that, both qualitatively and quantitatively, the metabolic profiles obtained with cynomolgus monkey liver samples were similar to those observed with human liver material. However, rat and dog were also confirmed to be suitable species for assessing the safety of mofarotene, and were used in toxicology. The involvement of cytochrome P450 (CYP) in the metabolism of mofarotene was examined with human liver microsomes. CYP3A4 plays a major role in the metabolism, and CYP1A2 might be responsible for a minor pathway. Finally, the potential induction by mofarotene of four major CYP isoenzymes was investigated in rats. These experiments showed that CYP1A1 was clearly induced, whereas a slight induction of CYP3A and CYP2B was observed. Repeated administration of mofarotene had no effect on CYP2E1. These studies with liver microsomes and hepatocytes aided the selection of appropriate species for toxicology, and have provided information that will help to predict potential drug-drug interactions in clinical trials.
芳维甲酸莫法罗汀是一种新型强效抗癌化合物。从大鼠、狗和人血浆中获得的代谢谱与在肝微粒体和肝细胞中观察到的相应体外谱显示出良好的相关性。使用从小鼠、大鼠、狗、食蟹猴和人的肝脏制备的微粒体研究了其代谢的种间差异。这些体外实验表明，无论是定性还是定量，食蟹猴肝脏样品获得的代谢谱与用人肝脏材料观察到的代谢谱相似。然而，大鼠和狗也被证实是评估莫法罗汀安全性的合适物种，并被用于毒理学研究。用人肝脏微粒体研究了细胞色素P450（CYP）在莫法罗汀代谢中的作用。CYP3A4在代谢中起主要作用，CYP1A2可能负责一条次要途径。最后，在大鼠中研究了莫法罗汀对四种主要CYP同工酶的潜在诱导作用。这些实验表明CYP1A1明显被诱导，而观察到CYP3A和CYP2B有轻微诱导。重复给予莫法罗汀对CYP2E1没有影响。这些对肝微粒体和肝细胞的研究有助于选择合适的毒理学研究物种，并提供了有助于预测临床试验中潜在药物相互作用的信息。
