Influence of sex and oestrogen replacement on the disposition of dexamethasone in rats

Abstract

The disposition of dexamethasone (DXM, 2 mg/kg, iv) was studied in ovariectomized female rats treated with oestrogen (0.1 mg and 1 mg of oestradiol benzoate) and in male rats. Oestradiol replacement had no effect on body or liver weights or on the DXM pharmacokinetic parameters (CL, Vdss, AUC, MRT and t1/2) of the female groups. If the Vdss seemed slightly greater in male than in female rats, this difference disappeared after normalization based on body weight. In contrast, CL was greater in the male rats even after normalization. For all the animals, significant correlations were observed between body weight and Vdss (r = 0.731, P less than 0.001) or CL (r = 0.639, P less than 0.001). Terminal half life and MRT were negatively correlated with CL (r = -0.481, P less than 0.01 and r = -0.575, P less than 0.01, respectively) but not with Vdss. Although oestrogen replacement did not seem to affect the pharmacokinetics of DXM, the increase in the CL in male rats should be the main determinant observed between the sexes. These results are consistent with a slower metabolism found for various drugs metabolized by the cytochrome P-450 in female rats.