Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes.
The oxidative metabolism of cinnarizine [(E)-1-(diphenylmethyl)-4-(3-phenyl-2-propyl)piperazine, CZ] and flunarizine [(E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propyl)piperazine, FZ] was examined in microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F-2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 microM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with Km values of 2 to 4 microM had intrinsic clearance values (Vmax/Km) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a Km value of 17 microM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.
Kariya
S
S
Department of Pharmaceutical Services, Tokyo Teishin Hospital, Japan.
Isozaki
S
S
Uchino
K
K
Suzuki
T
T
Narimatsu
S
S
D001402:B-Lymphocytes / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism*; D002460:Cell Line; D002936:Cinnarizine / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology*; D005444:Flunarizine / Q000378:metabolism*; D006801:Humans; D008861:Microsomes / Q000378:metabolism*; D010084:Oxidation-Reduction
D002121:Calcium Channel Blockers; D002936:Cinnarizine; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D005444:Flunarizine