Metabolism of antiparkinson agent dopazinol by rat liver microsomes

KP Vyas, PH Kari, HG Ramjit, SM Pitzenberger and M Hichens

Dept. of Drug Metabolism, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.

Metabolism of dopazinol (DZ) by liver microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats has been investigated. Liver microsomes from control and treated rats metabolized DZ to N-despropyl-DZ (39-53% of total metabolites); 8- hydroxy-DZ, a catechol metabolite (32-39%); and 5- or 6-hydroxy-DZ (12- 20%). The last metabolite was identified as its dehydration product 5,6- dehydro-DZ. N-Dealkylation was favored only slightly over catechol formation (ratio = 1.2) by liver microsomes from control and phenobarbital-treated rats, whereas with liver microsomes from 3- methylcholanthrene-treated rats, N-dealkylation predominated (ratio = 1.7). Liver microsomes from control rats metabolized DZ at a rate of 0.86 nmol/nmol cytochrome P-450/min. Pretreatment of rats with phenobarbital or 3-methylcholanthrene stimulated rates of metabolism by 2.4- and 3-fold, respectively. Metabolism of DZ was inhibited by SKF 525-A, methimazole, and thiobenzamide. SKF 525-A completely inhibited metabolism of DZ, while methimazole and thiobenzamide, two alternate substrates of the microsomal flavin-containing monooxygenase (MFMO) inhibited N-dealkylation only. These results indicated that while the cytochrome P-450-dependent monooxygenase is the primary enzyme system in DZ oxidation, the MFMO also catalyzes the N-dealkylation reaction. The catechol metabolite was converted to isomeric O-methylated derivatives in approximately 1:1 ratio by purified catechol-O-methyl transferase or 105,000g liver cytosol. The late eluting isomer was 8- methoxy-DZ.

Volume 18, Issue 6, pp. 1025-1030, 11/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics