Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes.
Article Details
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Kariya S, Isozaki S, Uchino K, Suzuki T, Narimatsu S
Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes.
Biol Pharm Bull. 1996 Nov;19(11):1511-4. doi: 10.1248/bpb.19.1511.
- PubMed ID
- 8951176 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Cinnarizine Cytochrome P450 1A1 Protein Humans UnknownSubstrateDetails Cinnarizine Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Cinnarizine Cytochrome P450 2A6 Protein Humans UnknownSubstrateDetails Cinnarizine Cytochrome P450 2B6 Protein Humans UnknownSubstrateDetails Cinnarizine Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Flunarizine Cytochrome P450 1A1 Protein Humans UnknownSubstrateDetails Flunarizine Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Flunarizine Cytochrome P450 2A6 Protein Humans UnknownSubstrateDetails Flunarizine Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Flunarizine Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareFlunarizinePhenytoin The therapeutic efficacy of Flunarizine can be increased when used in combination with Phenytoin. FlunarizineFosphenytoin The therapeutic efficacy of Flunarizine can be increased when used in combination with Fosphenytoin.