METABOLISM OF MOFAROTENE IN HEPATOCYTES AND LIVER-MICROSOMES FROM DIFFERENT SPECIES - COMPARISON WITH IN-VIVO DATA AND EVALUATION OF THE CYTOCHROME-P450 ISOENZYMES INVOLVED IN HUMAN BIOTRANSFORMATION

The arotinoid mofarotene is a novel potent anticancer compound, The me tabolic profiles obtained from rat, dog, and human plasma showed a goo d correlation with the corresponding in vitro profiles observed with l iver microsomes and hepatocytes. Interspecies differences in its metab olism were investigated using microsomes prepared from the livers of t he mouse, rat, dog, cynomolgus monkey, and humans. These in vitro expe riments showed that, both qualitatively and quantitatively, the metabo lic profiles obtained with cynomolgus monkey liver samples were simila r to those observed with human liver material. However, rat and dog we re also confirmed to be suitable species for assessing the safety of m ofarotene, and were used in toxicology. The involvement of cytochrome P450 (CYP) in the metabolism of mofarotene was examined with human liv er microsomes, CYP3A4 plays a major role in the metabolism, and CYP1A2 might be responsible for a minor pathway. Finally, the potential indu ction by mofarotene of four major CYP isoenzymes was investigated in r ats. These experiments showed that CYP1A1 was clearly induced, whereas a slight induction of CYP3A and CYP2B was observed. Repeated administ ration 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 predi ct potential drug-drug interactions in clinical trials.