title: Comparison of cytochrome p450 mediated metabolism of three central nervous system acting drugs.
abstract: The investigation of cytochrome P450 (CYP) mediated metabolism reactions by determination of enzyme kinetic parameters, Michaelis constant (K(m)), maximum reaction velocity (V(max)), and intrinsic clearance (CL(int)) is important aspects in discovery and development of drugs. The kinetic parameters can be used to predict the clearance prior to human administration and for better understanding the mechanism of clearance in vivo. In this study, the metabolic activities of three major hepatic CYP isoforms (2C19, 2D6, and 3A4) were investigated on structurally different central nervous system (CNS) acting drugs, amitriptyline, fluphenazine, and dothiepin. By using our novel in vitro evaluation system, we could compare the kinetic parameters for the metabolism of fluphenazine and dothiepin for the first time. Comparing CL(int) values thus obtained, we concluded that 2C19 could be predominant for metabolic activity on tricyclic antidepressants as expected, but not on phenothiazine-related antipsychotic drugs. Since the metabolism of CNS drugs is susceptible to single nucleotide polymorphisms of human gene, our results suggest that phenothiazine could be an alternative to clinical application of CNS drugs.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamadaoka, Suita, Osaka 565–0871, Japan.
authors.forename: Tamer Zekry
authors.initials: TZ
authors.lastname: Attia
authors.forename: Taku
authors.initials: T
authors.lastname: Yamashita
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Koizumi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yasuhara
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Node
authors.forename: Yumi
authors.initials: Y
authors.lastname: Erikawa
authors.forename: Yumi
authors.initials: Y
authors.lastname: Komiyama
authors.forename: Chiaki
authors.initials: C
authors.lastname: Horii
authors.forename: Mayu
authors.initials: M
authors.lastname: Yamada
authors.forename: Mahmoud Ahmed
authors.initials: MA
authors.lastname: Omar
authors.forename: Osama Hassan
authors.initials: OH
authors.lastname: Abdelmageed
authors.forename: Sayed Mohamed
authors.initials: SM
authors.lastname: Derayea
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Uno
mesh_terms: D000639:Amitriptyline / Q000737:chemistry / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D004308:Dothiepin / Q000737:chemistry / Q000378:metabolism*; D005476:Fluphenazine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D011994:Recombinant Proteins; D000639:Amitriptyline; D003577:Cytochrome P-450 Enzyme System; D005476:Fluphenazine; D004308:Dothiepin