title: Involvement of CYP2D6 in oxidative metabolism of cinnarizine and flunarizine in human liver microsomes.
abstract: Oxidative metabolism of cinnarizine (CZ) and its fluorine derivative flunarizine (FZ), both of which are selective calcium entry blockers, was examined in human liver microsomes. The ring-hydroxylations and the N-desalkylations constituted primary metabolic pathways in microsomal metabolism of CZ and FZ. Among these pathways, the ring-hydroxylase (p-hydroxylation) activities at the cinnamyl moiety of both drugs were highly correlated with debrisoquine 4-hydroxylase activity and CYP2D6 content. Quinidine, a selective inhibitor of CYP2D6, suppressed the ring-hydroxylase activities of CZ and FZ. These results suggest that CYP2D6 is involved in the ring-hydroxylation of the cinnamyl moiety of both CZ and FZ in human liver microsomes.
authors.affiliation: Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Narimatsu
authors.forename: S
authors.initials: S
authors.lastname: Kariya
authors.forename: S
authors.initials: S
authors.lastname: Isozaki
authors.forename: S
authors.initials: S
authors.lastname: Ohmori
authors.forename: M
authors.initials: M
authors.lastname: Kitada
authors.forename: S
authors.initials: S
authors.lastname: Hosokawa
authors.forename: Y
authors.initials: Y
authors.lastname: Masubuchi
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D001711:Biotransformation; D002936:Cinnarizine / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005444:Flunarizine / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011802:Quinidine / Q000494:pharmacology
chemical_list: D002936:Cinnarizine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D005444:Flunarizine