Effect of gonadectomy on cyclosporine pharmacokinetics in male and female rats

The present paper reports about the effect of gonadectomy on cyclosporine ( CyA) pharmacokinetics in rats. The oral administration of CyA (10 mg/kg b.w .) to male rats caused two-fold higher drug blood levels than those reached by females at 24 h after the last dose (334.10 +/- 126.70 vs. 161.49 +/- 5 3.39 ng/ml, p < 0.05). These levels increased by about 25% in orchiectomize d male rats (419.47 +/- 132.63 ng/ml) but they returned to control values a fter testosterone treatment (330.99 +/- 130.80 ng/ml). On the other hand, C yA blood levels (90.66 +/- 22.25 ng/ml) decreased after ovariectomy, even m ore in the case of gonadectomized female rats receiving estradiol replaceme nt (67.83 +/- 24.15 ng/ml). with regards to drug distribution, the concentr ations of CyA in the liver, the kidneys and the spleen at 24 h after the la st dose were about 8, 5 and 6-fold higher than blood levels, respectively, regardless of animal Sender. These partition coefficients were increased to 11, 7 and 9-fold by male castration suggesting a more extensive drug distr ibution. Contrariwise, drug tissue levels in ovariectomized rats decreased. The changes of drug blood and tissue levels among groups were not associat ed to the variations of metabolite concentrations in the liver or blood. Th erefore, gonadectomy exerts a complex effect on CyA pharmacokinetics in rat s and makes complementary studies necessary to clarify how differences in s exual hormone secretion alter CyA disposition.