Metabolism of a New 1,4-dihydropyridine Calcium Antagonist, Pranidipine, by cDNA-expressed Human Cytochrome P450.

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Abstract

To determine human cytochrome P450 isoform(s) (CYPs) involved in the metabolism of pranidipine, a new potent and long-acting 1, 4-dihydropyridine calcium antagonist, the biotransformation of the compound was investigated in vitro using ten isoforms of human cytochrome P450 expressed in human AHH-1 TK +/- cell lines. Modulation of an ethyl acetate-extract of grapefruit juice on the activity of CYP3A4-mediated pranidipine metabolism was also investigated.<BR> 1. Pranidipine was dehydrogenated into pyridine metabolite by CYP3A4 with Km and Vmax values of 21.4 μM and 0.110 nmol/min/mg protein, respectively. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 were not involved in the pranidipine metabolism.<BR> 2. MOP-13031 constructed with dihydropyridine ring, a metabolite of pranidipine, was also oxidized into pyridine ring by the multi-isoforms of cytochrome P450 including CYP3A4, 2C19, 2D6 and 2E1. The Km and Vmax values on the oxidation of MOP-13031 to pyridine metabolite by CYP3A4 were 796 μM and 0.124 nmol/min/mg protein, respectively.<BR> 3. CYP3A4-mediated testosterone 6β-hydroxylase activity was competitively inhibited by pranidipine with a Ki value of 5.44 μM but was not affected by MOP-13031 up to a concentration of 100 μM. (±) Miconazole inhibited the hydroxylation up to 94.7% at 10 μM.<BR> 4. CYP3A4-mediated pranidipine dehydrogenase activity was dose-dependently decreased by an addition of the ethyl acetate-extract of grapefruit juice.

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