Interspecies variability and drug interactions of clozapine metabolism by microsomes

Cytochrome P450 expression in liver is influenced by several factors, inclu ding species, sex and strain. We compared metabolism formation of clozapine in different species (rat, mouse, guinea-pig, dog, monkey;md man) so as to choose between species to further validate interaction studies. Liver micr osomes of male and female Sprague-Dawley rats, hairless rats, OF1 mice, Bal b C mice and Dunkin-Hartley albino guinea-pigs, male beagle dogs, male cyno molgus monkeys and man were used to investigate in vitro metabolism of cloz apine. This process was dependent on the presence of NADPH and on the prese nce of microsome protein. In addition, we observed the formation of desmeth yl- and N-oxide metabolites, with the rate of formation of each of these co mpounds varying with species, sex and strain of microsomes incubated. The d esmethyl and N-oxide metabolites formed were statistically greater in male than in female rats, mice in the two strains studied, as well as for the gu inea-pigs. Levels of desmethyl. clozapine formed were high for the rats and no significant difference in clozapine biotransformation was observed betw een Sprague Dawley and hairless rats. For man, the formation of metabolites of clozapine was comparable with guinea-pig, dog and monkey. In addition, we screened the effect of 52 molecules, representative of 11 different ther apeutic classes, on the metabolism of clozapine by rat liver microsomes. We found that most of the calcium channel blockers (diltiazem, felodipine, is radipine, lacidipine, nicardipine and nitrendipine), antifungals (ketoconaz ole, miconazole) and two anticancer drugs (paclitaxel, teniposide) caused m ore than 50% inhibition of clozapine metabolism in vitro. The extent of inh ibition was increased in a concentration-dependant manner. Complementary cl inical and pharmacokinetic studies should be performed to confirm these res ults. (C) 1999 Editions scientifiques et medicales Elsevier SAS.