In vivo effect of 5- and 8-methoxypsoralens and cimetidine on R,S-warfarin metabolism in rat.
Several forms of cytochrome P-450 (CYP) metabolize R,S-warfarin in a regio- and enantioselective manner, therefore R,S-warfarin can be recognized as a metabolic probe for a number of CYP isoforms. We have applied a warfarin model in vivo in order to estimate the inhibitory properties of 5- and 8-methoxypsoralens on the activity of rat CYP isoforms. The area under the serum concentration versus time curve (AUC) values from time zero to 5 h for R- and S-warfarin and their metabolites were calculated. R,S-Warfarin kinetics measurements were made three times on each rat: a week before the 7-days inhibitor treatment, 3 h after the last dose of inhibitor and 3-7 days after the inhibitor was withdrawn. The inhibitory effect of cimetidine on CYP 2C11 and CYP 2C6 activities was confirmed in this approach and can be recognized as a positive control in validation of the in vivo experiment. Both 5- and 8-methoxypsoralen inhibited CYP 2C6 activity as the respective AUC for metabolite/warfarin enantiomer ratio decreased significantly. The activity of CYP 2C6 in 5- and 8-methoxypsoralen-treated rats increased over control values after the inhibitor was withdrawn. It was also observed that cimetidine additionally inhibits the absorption of R,S-warfarin and a decrease in the sum of AUC for R- and S-enantiomers became evident in spite of inhibition of the activity of both CYPs. 5-Methoxypsoralen modified the serum R-warfarin/S-warfarin ratio and a selective increase in AUC(S-warfarin) was observed, the most pronounced being after the inhibitor was withdrawn. This effect is not likely to be mediated by P-glycoprotein (P-gp) because quinidine--, a P-gp inhibitor at a dose of 15 mg kg(-1) body wt.--did not influence the AUC for either enantiomer.
D000078223:5-Methoxypsoralen; D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008730:Methoxsalen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014859:Warfarin / Q000493:pharmacokinetics*
D000925:Anticoagulants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000078223:5-Methoxypsoralen; D014859:Warfarin; D002927:Cimetidine; D008730:Methoxsalen