Comparative metabolism of mecloqualone-2-14C in mice, rats, dogs and man

Abstract

A comparative study of the metabolism of mecloqualone (I) was carried out in mice, rats, dogs and man by use of the radioactive drug, 3-(o-chlorophenyl)-2-methyl-4[3H]-quinazolinone-2-14C. It is excreted in both urine and feces almost entirely as metabolites by all the species without loss of the 14C as 14CO2. Biliary excretion was demonstrated in rats. After hydrolysis of the conjugated metabolites in the urines with β-glucuronidase, 26–45% of the 14C-labeled metabolites (depending on the species) could be extracted with benzene. The metabolites in benzene extracts were identified by a combination of methods including quantitative thin-layer chromatography, countercurrent distribution, inverse isotope dilution and, when present in a sufficient amount, direct crystallization. The metabolic pathways and metabolites are: hydroxylation of the 2-methyl, 3-(o-chlorophenyl)-2-(hydroxymethyl)-4[3H]-quinazolinone (II); hydroxylation of the quinazolinone ring in the anthranilic acid moiety, 3-(o-chlorophenyl)-6-hydroxy-2-methyl-4[3H]-quinazolinone (III); and hydroxylation of the o-chlorophenyl ring, 3-(2-chloro-4-hydroxyphenyl)-2-methyl-4[3H]-quinazolinone (IV). Compounds I, II, III and IV were excreted in the following amounts as percent of the 14C in the urine collected up to 48 hr, respectively: mice (female, Swiss) 1, 5, 10 and 6; rats (male, Wistar descendant) 1, 26, 9 and 3; dogs (male, mongrel) <0.5, 6, 2, 18; humans (male) 0.5, 4, 3 and 17. Thus, although all the identified metabolites were excreted by all the species, the phenolic metabolite (IV) is the principal one in the benzene extract of urine in man and dogs, while in rodents it is the alcohol (II). However, the phenolicmetabolites (III and IV) were a more important component in collections of rat bile.