Sex-related differences in the renal disposition of the acidic metabolite of clentiazem in rat

Abstract

1. Sex-related differences in the renal excretion of the acidic compounds (+)-(2 S, 3 S) 8-chloro-2,3,4,5-tetrahydro-3-hydroxy-2-(4-hydroxyphenyl)-4-oxo-1,5-benzothiaz 5-acetic acid (MA4; one of the acidic metabolites of clentiazem), probenecid (PB) and methotrexate (MTX) have been investigated in the 7-week-old male and female SpragueDawley rat using an in vivo renal clearance technique. 2. The extent of plasma protein binding of MA4, PB and MTX was ~96, 95 and 65%, respectively, and it did not differ significantly between the male and female rat. On the other hand, the unbound renal clearance (CLrf) of MA4 in the female was ~300 times higher than that in male, and the ratio of this clearance to the glomerular filtration rate (GFR) was ~10, suggesting that MA4 undergoes extensive active renal secretion in the female. Furthermore, the CLrf/GFR ratio was significantly decreased by co-administration of PB. In contrast, no sex-related difference in the renal excretion of PB could be detected because its CLrf was very low and reabsorption contributed extensively to its renal disposition. The CLrf/GFR for MTX was ~2.5 but did not differ significantly between the male and female. 3. The renal organic anion transport systems in rat show sex-related differences and have different substrate-specific characteristics.