title: Metabolism of antiparkinson agent dopazinol by rat liver microsomes.
abstract: 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.
authors.affiliation: Dept. of Drug Metabolism, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
authors.forename: P H
authors.initials: PH
authors.lastname: Kari
authors.forename: H G
authors.initials: HG
authors.lastname: Ramjit
authors.forename: S M
authors.initials: SM
authors.lastname: Pitzenberger
authors.forename: M
authors.initials: M
authors.lastname: Hichens
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008745:Methylation; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000978:Antiparkinson Agents; D010078:Oxazines; C042631:naxagolide; D008748:Methylcholanthrene; D010634:Phenobarbital