Sex-related differences in urinary excretion of egualen sodium in rats

Egualen sodium (sodium 3-ethyl-7-isopropyl-1-azulenesulfonate 1/3 hydrate) is a new antiulcer drug. There has been no difference observed in absorption between male and female rats, the relative amount of metabolites in male plasma has been higher than that in females, and the excretion ratios of metabolites in males have been significantly higher than those in females. However, the plasma concentration profile of total radioactivity in males has been higher than that in females. To clarify this discrepancy, the renal clearances and plasma concentrations of the unchanged drug and its metabolites were determined. The renal clearance of the unchanged drug in males was 21 times lower than that in females, and the urinary excretions in males and females were 2.1 and 39.5% of dose, respectively. This indicates that the major factor in the sex-related difference observed in the plasma concentration of total radioactivity is due to the difference in the renal clearance of the unchanged drug between the sexes. The results of treatments with probenecid in normal and gonadectomized rats revealed that egualen sodium was mainly excreted into urine by secretion through the renal tubule. Furthermore, the results of treatments with testosterone in rats revealed that the excretion of egualen sodium was highly affected by androgens. These facts indicated that the sex-related difference observed in the plasma concentration of total radioactivity can be attributed to the inhibition of renal tubular secretion of the unchanged drug by androgens. This is the first example of sex-related differences in both metabolism and excretion.