Age-dependent differences in the effect of phenprocoumon on the vitamin K1-epoxide cycle in rats

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Abstract
The anticoagulant activity and the pharmacokinetics of phenprocoumon as well as the effect of phenprocoumon on the vitamin K1-epoxide cycle in younger (12 weeks) and older (36 weeks) male inbred Lewis rats has been examined in a study of the mechanism responsible for the increase in the responsiveness to oral anticoagulant drugs (OAD's) with increasing age. After a single i.v.-dose of phenprocoumon (0†355 mg kg−1 the anticoagulant effect obtained was greater in older than in younger rats. There were no differences between younger and older rats in the rate of elimination, volume of distribution and in the free fraction and free concentration values of phenprocoumon in plasma and liver. After i.v.- injection of 64·3 μg kg−1 [3 H]vitamin K1 and different doses of phenprocoumon (0·02 to 3 mg kg−1) the [3 H]vitamin K1 concentration in the liver decreased and the [3 H] vitamin K1-2, 3-epoxide concentration increased dependent on the dose and the liver concentration of phenprocoumon. These changes were more pronounced in the older than in the younger rats. Concentration-response curves gave similar EC50-values for both age-groups but a 1·6-fold higher maximal response (expressed as vitamin K1-epoxide/vitamin K1 ratios) in the older rats. Since OAD's exert their anticoagulant effect most probably by inhibiting an enzyme (vitamin K1-epoxide reductase) which regenerates vitamin K1 from the epoxide metabolite and since the vitamin K1-epoxide/vitamin K1 ratios in the liver may reflect the degree of inhibition of the epoxide reductase by OAD's, our results may indicate that the inhibitory effect of phenprocoumon on this enzyme is more pronounced in older than in younger rats. This could explain the age-dependent differences in the anticoagulant activity.