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

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 less than 0.001) as well as a lower apparent volume of distribution (288 +/- 46 vs 617 +/- 105 mL kg-1; t = 7.58, P less than 0.001) and a longer half-life (25.5 +/- 3.4 vs 17.5 +/- 1.8 h; t = 5.16, P less than 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 less than 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 less than 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 less than 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.

Pharmacokinetics of Moclobemide in Male, Virgin Female, Pregnant and Nursing Rats

“…The data suggest that male rats may have an intrinsic hepatic clearance approximately twice that of female rats (107 vs 42 mL min-I kg-I) using the well-stirred model (Pang & Rowland 1977). Gender differences in metabolic rates of drugs involving the P450 system are well known in the rat (Pyorala 1968;Kato 1974;Vodicnik et a1 1981;Billings 1983;Trenk et al 1988) and are often attributed to sex-hormonedependent P450 isoenzymes Kamataki et al 1982). At present there is no indication of a gender-related difference in man.…”

Has bovine somatotropin (BST) an effect upon drug disposition? Comparative studies in goats and cattle with sulphadimidine and antipyrine after parenteral administration of BST, zeranol and proligestone

“…In women, oral contraceptives have been shown to signifi-cantly change the clearance of several drugs (Briggs & Briggs, 1981;Abernathy et al, 1982;Legner & Bennet, 1982;Jochemsen et al, 1982;Teunissen et al, 1982;Tornatore et al, 1982;Stoehr et al, 1984; Van der Kuy & Merkus, 1987;Bachmann et al, 1987) and this therefore confirms the general finding in laboratory species that low doses of sex hormones can affect drug disposition. In the rat, the duration and intensity of drug action is often greater in the adult female than in the adult male (Conney, 1974;Kato, 1974;Gustafsson el al., 1983;Kane & Chen, 1987;Trenk et al, 1988;Waxman, 1988). Young adult male rats' metabolize drugs much faster than mature female rats or pre-pubertal male rats.…”