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 three alkylamine-type antihistamines; brompheniramine, chlorpheniramine and pheniramine. 2. Based on the amount of parent drug recovered after 168 h of incubation, C. elegans ATCC 9245 metabolized 60, 45 and 29% of brompheniramine, chlorpheniramine and pheniramine added respectively. The results from strain ATCC 36112 were essentially identical to those 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 antihistamines, the mono-N-demethylated metabolite was produced in the greatest amounts. The chloro- and bromo-substituents appeared not to affect the route of metabolism but did influence the relative amounts of metabolites produced. 4. Circular dichroism spectra of the metabolites and the unmetabolized parent antihistamines showed each to be a racemic mixture of the (+) and (-) optical isomers. In addition, comparison of the metabolism of racemic chlorpheniramine to that of optically pure (+) chlorpheniramine showed no significant differences in the ratios of metabolites produced. There was therefore no metabolic stereoselectivity observed by the fungal enzymes.