Biotransformation of terodiline. III. Opposed stereoselectivity in the benzylic and aromatic hydroxylations in rat liver microsomes

Abstract

1. Terodiline (N-tert-butyl-4,4-diphenyl-2-butylamine) is a racemic drug with anti-cholinergic and/or calcium antagonistic activity, which is subject to renewed interest as a potential remedy for urinary incontinence. As part of the current investigations on terodiline, the metabolism of its enantiomers is being investigated. 2. The metabolism of the enantiomers of terodiline in rat liver microsomes is slow, as for the racemate, though the S-enantiomer is metabolized more rapidly than its optical antipode. Phenobarbitone pretreatment of the rats enhances the metabolism with a marked increase in the conversion of the S-enantiomer. 3. While aromatic p-hydroxylation greatly exceeds benzylic oxidation in the metabolism of R-terodiline, this situation is reversed in the metabolism of S-terodiline. Moreover, the rate of aromatic p-hydroxylation of racemic terodiline follows that of R-terodiline, while the rate of benzylic hydroxylation of racemic terodiline follows that of S-terodiline. Phenobarbital pretreatment of the rats had little or no effect on aromatic p-hydroxylation but markedly increased benzylic oxidation. 4. Separation of the mixture of p-hydroxylated metabolites into diastereomeric pairs showed that their composition is highly dependent on which form of terodiline is used as substrate. 5. The results from the study are compatible with the participation of multiple forms of cytochrome P-450 enzymes.