An investigation of sex-linked differences to the toxic and to the pharmacological actions of difenacoum: studies in mice and rats

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Abstract
We have investigated the actions of the coumarin anticoagulant, difenacoum, in male and female rats and mice. In our first experimnt difenacoum (0.5 mg kg−1) killed 50% of male mice within 9 days of its administration, whereas no female mice died during this study. In a second group of experiments, the anticoagulant effect of difenacoum in male and female rats was determined. Under resting conditions, the prothrombin complex activities (PCA) of male and female rats were not significantly different. Over the first 24 h after administration of difenacoum (0.4 mg kg−1 i.p.), there was a monoexponential fall in PCA in both sexes. However, 6, 12 and 24 h after difenacoum, the PCA in male rats was significantly (P <0.05) lower than in female rats. PCA began to recover over the subsequent 48 h in both sexes, during which time there was marked variability in recovery in female rats. The difference between the onset of action of difenacoum in male and female rats did not appear to be due to a greater rate of elimination of the drug in female rats, since the plasma concentrations of difenacoum 24 h after its administration were the same in both sexes. The concentration of vitamin K1 in rat liver was also investigated. Vitamin K1 levels were 35.1 ± 18.6 ng (g liver)−1 (male), and 29.4 ± 5.4 ng (g liver)−1 (females) in control rats, but 24 h after difenacoum, vitamin K1 levels were either very low, or undetectable in all rats. It is, therefore, possible that the difference between the responses to difenacoum in males and females was due to a greater rate of breakdown of vitamin K-dependent clotting factor precursors in male rats and mice, compared with female rats and mice.