Sex Differences in Renal Excretion of Drugs

Abstract

Sex difference in the elimination of drugs can be due to either a difference in excretion or in metabolism. Sex differences in drug metabolism are well known and occur in both phase I and II metabolism, while the situation with excretion, especially renal excretion, is unclear.
Zenarestat, [3-(4-bromo-2-fluorobenzyl)-7-chloro-2, 4-dioxo-1, 2, 3, 4-tetrahydroquinazolin-1-yl] acetic acid is an aldose reductase inhibitor. Rat shows a marked sex difference in the excretion of ¹⁴C-zenarestat: only 1 % of the dose was excreted in the urine of males, about 45% of the dose was excreted in the urine of females. ¹⁴C in the urine of female rats was almost entirely unchanged drug. Renal clearance experiments, and inhibition of urinary excretion by probenecid, indicated that female rats may possess an active secretory mechanism which is lacking or relatively inactive in male rats.
Castration of male rats at 22 days of age abolished th e adult sex difference in urinary excretion of zenarestat, while castration at 5 weeks of age produced urinary excretion of the drug about half that in females. Ovariectomy of females at 22 days or 5 weeks of age had no effect on the urinary excretion of zenarestat. Treatment of male and female gonadectomized rats with testosterone resulted in the urinary excretion of zenarestat characteristic of intact adult male rats.
Hypophysectomized male rats and normal female rats has similar urinary excretion of zenarestat which was much greater than that of normal male rats. Treatment of male and female hypophysectomized rats with testosterone resulted in the urinary excretion of zenarestat characteristic of intact adult male rats. Urinary secretion of zenarestat in rats is independent of pituitary hormone and is suppressed only by androgen.
Urinary excretion of zenarestat scarcely differed between 3-week-old male and female rats; it decreased in males from 4 weeks of age, but in females urinary excretion of the drug was essentially constant during ageing.
Mice show a sex difference in the excretion of zenarestat similar to that seen in rats, but dogs and humans show no significant sex difference. Female rats and mice, and both sexes of dogs and humans, appear to possess an active secretory mechanism in the renal excretion of zenarestat, which is lacking or relatively inactive in male rats and mice.
The effect of acute ( ?? 1 week) and chronic ( ?? 3 weeks) streptozocin induced diabetes on the pharmacokinetics of zenarestat was studied in male and female rats. In male acute and chronic diabetic rats, the urinary excretion increased compared with the control after the dose with ¹⁴C-zenarestat. It did not change in female acute diabetic rats and decreased in female chronic diabetic rats compared with the control. Renal clearance experiments suggested that the decrease in urinary excretion in female chronic diabetic rats is due to a decrease in active secretion. The increase in the urinary excretion in male rats was probably due to a decrease in testostereone levels in the diabetic state.