FUNGAL TRANSFORMATIONS OF ANTIHISTAMINES - METABOLISM OF BROMPHENIRAMINE, CHLORPHENIRAMINE, AND PHENIRAMINE TO N-OXIDE AND N-DEMETHYLATED METABOLITES BY THE FUNGUS CUNNINGHAMELLA-ELEGANS

1. Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were screened for their ability to metabolize thr ee alkylamine-type antihistamines; brompheniramine, chlorpheniramine a nd pheniramine. 2. Based on the amount of parent drug recovered after 168 h of incubation, C. elegans ATCC 9245 metabolized 60, 45 and 29% o f brompheniramine, chlorpheniramine and pheniramine added respectively . The results from strain ATCC 36112 were essentially identical to tho se of strain ATCC 9245. 3. The metabolic products of N-oxidation and N -demethylation were isolated by reversed-phase hplc and identified by analysing their mass and proton nmr spectra. For all three antihistami nes, the mono-N-demethylated metabolite was produced in the greatest a mounts. The chloro- and bromo-substituents appeared not to affect the route of metabolism but did influence the relative amounts of metaboli tes produced. 4. Circular dichroism spectra of the metabolites and the unmetabolized parent antihistamines showed each to be a racemic mixtu re of the (+) and (-) optical isomers. In addition, comparison of the metabolism of racemic chlorpheniramine to that of optically pure (+) c hlorpheniramine showed no significant differences in the ratios of met abolites produced. There was therefore no metabolic stereoselectivity observed by the fungal enzymes.