Interaction of cytochrome P450 2C19 with benzodiazepines in vitro: Flunitrazepam identified as a substrate of CYP2C19

grantor: University of TorontoFluintrazepam (Rohypnol$\sp\circler$) is an abused benzodiazepine that has gained notoriety in North America as the "date rape" drug because it causes memory loss and sedation in women who are surreptitiously given the drug. Differences in sensitivity to fluintrazepam are not known. The interaction of various benzodiazepines with cytochrome P450 2C19 and metabolism of flunitrazepam in human liver microsomes were investigated. CYP2C19 is polymorphically expressed in human populations and metabolizes many therapeutically important drugs (e.g., diazepam, omeprazole). 23% of Japanese and 3% of Caucasians lack CYP2C19 activity because of mutations in the gene coding for CY2PC19. We hypothesized that fluintrazepam is metabolized by CYP2C19. Omeprazole was used as the probe drug to characterize CYP2C19 and CYP3A4 activity by quantitating 5-hydroxyomeprazole (5-OHOMP)(CYP2C19) and omeprazole sulphone (CYP3A4) formation. Omeprazole kinetics in African-green monkey liver microsomes were also studied and are comparable to that in human liver. Formation of 5-OHOMP and omeprazole sulphone was inhibited by various benzodiazepines in human and African-green monkey liver microsomes and respective K$\sb{\rm i}$ values determined. (Abstract shortened by UMI.)M.Sc