Metabolism of carteolol by cDNA-expressed human cytochrome P450.

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Kudo S, Uchida M, Odomi M

Metabolism of carteolol by cDNA-expressed human cytochrome P450.

Eur J Clin Pharmacol. 1997;52(6):479-85.

PubMed ID

9342584 [ View in PubMed

]

Abstract

OBJECTIVES: To determine human cytochrome P450 isoform(s) (CYPs) involved in the metabolism of carteolol, the biotransformation of the compound was investigated in vitro using ten isoforms of human cytochrome P450 expressed in human AHH-1 TK +/- cell lines. In addition, the inhibitory effects of carteolol on the activities of important CYP isoforms, namely, CYP1A2, 2C9, 2C19, 2E1, and 3A4, were examined. RESULTS: Carteolol was metabolised to 8-hydroxycarteolol by CYP 2D6 with KM and Vmax values of 183 mumoles.l-1 and 26.09 pmol.min-1.pmol-1 P450, respectively. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4 were not involved in the metabolism of the compound. CYPD6-mediated carteolol 8-hydroxylase activity was inhibited by quinidine, propranolol, nortriptyline, dextromethorphan, sparteine, bufuralol, and biperiden. Biperiden competitively inhibited the catalytic reaction with a Ki value of 0.45 mumoles.l-1. Carteolol did not affect the following catalytic reactions: CYP1A2-mediated (R)-warfarin 6-hydroxylation, CYP2C9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated (S)-mephenytoin 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6 beta-hydroxylation. CONCLUSION: 8-Hydroxylation is the only cytochrome P450-catalyzed metabolic reaction of carteolol by its expressed microsomes, and CYP2D6 is the principal isoform of the enzyme involved in the catalytic reaction. Carteolol has neither stimulative nor inhibitory effects on CYP1A2, 2C9, 2C19, 2E1, and 3A4 activities.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Biperiden	Cytochrome P450 2D6	Protein	Humans	Unknown	Inhibitor	Details
Carteolol	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate	Details