CHARACTERIZATION OF THE CYTOCHROME-P450 ENZYMES INVOLVED IN THE IN-VITRO METABOLISM OF GRANISETRON

1 The metabolism of granisetron was investigated in human liver micros omes to identify the specific forms of cytochrome P450 responsible. 2 7-hydroxy and 9'-desmethyl granisetron were identified as the major pr oducts of metabolism following incubation of granisetron with human li ver microsomes. At low, clinically relevant, concentrations of granise tron the 7-hydroxy metabolite predominated. Rates of granisetron 7-hyd roxylation varied over 100-fold in the human livers investigated. 3 En zyme kinetics demonstrated the involvement of at least two enzymes con tributing to the 7-hydroxylation of granisetron, one of which was a hi gh affinity component with a K-m of 4 mu M. A single, low affinity, en zyme was responsible for the 9'-desmethylation of granisetron. 4 Grani setron caused no inhibition of any of the cytochrome P450 activities i nvestigated (CYP1A2, CYP2A6, CYP2B6, CYP2C918, CYP2C19, CYP2D6, CYP2E1 and CYP3A), at concentrations up to 250 mu M. 5 Studies using chemica l inhibitors selective for individual P450 enzymes indicated the invol vement of cytochrome P450 3A (CYP3A), both pathways of granisetron met abolism being very sensitive to ketoconazole inhibition. Correlation d ata were consistent with the role of CYP3A3/4 in granisetron 9'-desmet hylation but indicated that a different enzyme was involved in the 7-h ydroxylation.