title: Metabolism of N,N-dipropyl-2-[4-methoxy-3-(2-phenyl-ethoxy)-phenyl]-ethyl-amine-monohydrochloride (NE-100), a novel sigma ligand: contribution of cytochrome P450 forms involved in the formation of individual metabolites in human liver and small intestine.
abstract: In the present study, human cytochrome P450 (CYP) forms involved in producing the primary metabolites of NE-100 were identified. Major metabolites of NE-100 in human liver microsomes (HLM) were N-depropylation of NE-100 (NE-098), p-hydroxylation of phenyl group of NE-100 (NE-152), m-hydroxylation of phenyl group of NE-100 (NE-163) and O-demethylation of NE-100 (NE-125). Judging from the correlation and inhibition studies, NE-125 and NE-152+163mix formations were predominantly mediated by CYP2D6 and NE-098 formation was mediated by multiple CYP forms at a low NE-100 concentration (0.1 microM) in the HLM. According to relative activity factor (RAF) approaches, all these reactions were predominantly catalyzed by CYP2D6 at a substrate concentration assuming a plasma level of NE-100 (K(m)>>S) in case of the human liver. Depending on the increase in NE-100 concentrations, the rate of contribution for NE-098 and NE-152+163mix formations increased in CYP3A4, although the predominant contribution of CYP2D6 for NE-125 formation did not change. In human intestinal microsomes (HIM), NE-100 was mainly metabolized to NE-098 and NE-152+163mix by CYP3A4. The intrinsic clearance for their formations in HIM was 3.2 and 14.9 times less than those in HLM, respectively, and no formation of NE-125 was observed in HIM. These results strongly suggest that CYP2D6 is the predominant form for NE-100 metabolism in the human liver in in vivo conditions (K(m)>>S) and the liver plays a more important role than does the small intestine in the first pass metabolism.
authors.affiliation: Department of Drug Metabolism, Medicinal Research Laboratory, Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan. takahito.yamamoto@po.rd.taisho.co.jp
authors.forename: Takahito
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Hagima
authors.forename: Misako
authors.initials: M
authors.lastname: Fukasawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Yamaguchi
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Kohno
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe