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

1. Sex-related differences in the renal excretion of the acidic compounds (+)-(2S,3S)-8-chloro-2,3,4,5-tetrahydro-3-hydroxy-2-(4-hydroxyphenyl)-4-oxo-1,5-benzothiazepin-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 Sprague-Dawley rat using an in vivo renal clearance technique. 2. The extent of plasma protein binding of MA4, PB and MTX was similar to 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 similar to 300 times higher than that in male, and the ratio of this clearance to the glomerular filtration rate (GFR) was similar to 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 similar to2.5 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.