Abstract

The pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, M-III of resatorvid, in rats and dogs were investigated using radiolabeled M-III ([¹⁴C]M-III). The elimination half-life of ¹⁴C in the plasma of rats was approximately 1/30 of that of dogs after intravenous dosing of [¹⁴C]M-III at 0.5 mg/kg to rats and dogs. The in vitro and in vivo plasma protein binding ratios of M-III were relatively high and were the same in both species. The intrinsic clearance (CL_int) of M-III in rats was much higher than the glomerular filtration rate in rats. Furthermore, the concentration of [¹⁴C]M-III in the kidney of rats was much higher than that in the plasma. On the contrary, in dogs, the concentration of [¹⁴C]M-III in the kidney was very much lower than that in the plasma. These results indicated that M-III was effectively taken up into the kidney and was excreted into the urine in rats; however, in dogs, ineffective renal uptake of M-III was presumed. When [¹⁴C]M-III and probenecid were simultaneously and continually infused intravenously to rats, the CL_int of M-III decreased with increasing plasma concentrations of probenecid, indicating that kidney uptake of M-III in rats was inhibited by probenecid. It was also thought that uptake by the organic anion transport system(s) in the basolateral membrane is involved in the renal uptake of M-III in rats. The pharmacokinetic differences of M-III between rats and dogs are considered to be mainly caused by the difference in the urinary excretion via the renal distribution processes.