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RESEARCH PRODUCT

Sex-related Differences in Disposition and Response to Phenprocoumon in Rats

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Abstract The pharmacokinetics and the pharmacological response to phenprocoumon have been studied in female and male inbred Lewis-Wistar rats. A significantly lower clearance was found in female than in male rats (7.9 ± 1.4 vs 24.5 ± 2.5 mL h−1 kg−1, respectively; t = 15.09, P < 0.001) as well as a lower apparent volume of distribution (288 ± 46 vs 617 ± 105 mL kg−1; t = 7.58, P < 0.001) and a longer half-life (25.5 ± 3.4 vs 17.5 ± 1.8 h; t = 5.16, P < 0.001). The binding of phenprocoumon was higher in female than in male rats (fu: 0.0096 ± 0.0008 vs 0.0124 ± 0.0007, respectively; t = 6.66, P < 0.001). The total (C) as well as the unbound concentration (Cu) needed to elicit a 50% decrease in the prothrombin complex synthesis rate was substantially higher in female rats: C50 was 377 ± 98 ng mL−1 in female and 155 ± 29 ng mL−1 in male rats (t = 5.32, P < 0.001), whereas Cu50 was 3.6 ± 0.7 ng mL−1 in female and 1.9 ± 0.3 ng mL−1 in male rats (t = 5.50, P < 0.001). However, because of the lower clearance and volume of distribution and the longer half-life in female rats, the female rats experienced a higher cumulative effect than male rats to 0.34 mg kg−1 i.v. doses.