Metabolism of procyclidine in isolated rat hepatocytes.

1. The biotransformation of procyclidine in isolated hepatocytes, prepared from untreated and from phenobarbital-pretreated rats, is described. 2. Major metabolic pathways are ketone formation on carbon-4 and monohydroxylation in cis-4, trans-4 and (1R*, 3R*, 7S* (or R*))-trans-3 positions of the cyclohexyl ring. 3. Minor pathways consist of monohydroxylation in (1R*, 3S*, 7R*)- and (1R*, 3S*, 7S*)-cis-3 and vicinal diol formation in (1R*, 3R*, 4S*, 7R* (or S*))-cis-3, cis-4 and (1R*, 3S*, 4R*, 7S* (or R*))-trans-3, trans-4 positions of the cyclohexyl part of the molecule. 4. After phenobarbital treatment monohydroxylation in cis-4, trans-4 and trans-3 and vicinal diol formation in trans-3, trans-4 positions are significantly increased and the cis-4 to trans-3 ratio is reversed. 5. The hypothesis is made that the monohydroxylations in cis-3 and trans-3 represent an intermediate step in the formation of the dihydroxycyclohexyl metabolites, since this pathway is not observed in vivo. The hypothesis is supported by incubation experiments of synthetic monohydroxycyclohexyl derivates of procyclidine with isolated rat hepatocytes.