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Drug Metab Dispos. 1997 May;25(5):623-30.

Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P4503A (CYP3A) subfamily.

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Drug Metabolism Department, Abbott Laboratories, USA.


In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) protein(s) involved in the oxidative metabolism of [14C]clarithromycin (CLAR) in the presence of native human liver microsomes. The identity of the two major CLAR metabolites present in microsome incubates, 14-(R)-hydroxy-CLAR and N-desmethyl-CLAR, was confirmed by MS. Over the CLAR concentration range of 1.0-140 microM, the rate of CLAR 14-(R)-hydroxylation (KM = 48 +/- 17.7 microM; Vmax = 206 +/- 76 pmol/min/mg protein; Vmax/KM = 4.2 +/- 0.21 microliters/min/mg; mean +/- SD, N = 3 livers) and N-demethylation (KM = 59.1 +/- 24.0 microM; Vmax = 189 +/- 52.0 pmol/min/mg protein; Vmax/KM = 3.3 +/- 0.53 microliters/min/mg) conformed to monophasic (saturable) Michaelis-Menten kinetics and was highly correlated (r = 0.90-0.92; p < 0.001; N = 11) with CYP3A-selective erythromycin N-demethylase activity. Ketoconazole (< or = 2.0 microM) or troleadomycin, CYP3A-selective inhibitors, markedly decreased (> or = 99%) the formation of both metabolites, whereas inhibitors selective of other CYP forms were relatively ineffective (< or = 10% inhibition). In agreement with chemical inhibitor studies, CLAR metabolism was only detectable with human B-lymphoblastoid microsomes containing cDNA-expressed CYP3A4 (vs. CYP2C19, CYP2C9, CYP2D6, CYP1A2, CYP2E1, or CYP2A6). Furthermore, the apparent KM characterizing the 14-(R)-hydroxylation and N-demethylation of CLAR in the presence of insect cell microsomes containing cDNA-expressed CYP3A4 (KM = 18-63 microM) was similar to that obtained with native human liver microsomes. Based on the results of this study, it is concluded that the 14-(R)-hydroxylation and N-demethylation of CLAR is primarily mediated by one or more members of the human liver CYP3A subfamily.

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