In vivo effect of 5‐ and 8‐methoxypsoralens and cimetidine on R,S‐warfarin metabolism in rat

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Abstract
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a week before the 7‐days inhibitor treatment, 3 h after the last dose of inhibitor and 3–7 days after the inhibitor was withdrawn.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The activity of CYP 2C6 in 5‐ and 8‐methoxypsoralen‐treated rats increased over control values after the inhibitor was withdrawn.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ratio and a selective increase in AUCS−warfarin was observed, the most pronounced being after the inhibitor was withdrawn.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. Copyright © 2002 John Wiley & Sons, Ltd.

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