Differences in the pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, a metabolite of resatorvid, in rats and dogs.
The pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, M-III of resatorvid, in rats and dogs were investigated using radiolabeled M-III ([(14)C]M-III). The elimination half-life of (14)C in the plasma of rats was approximately 1/30 of that of dogs after intravenous dosing of [(14)C]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 [(14)C]M-III in the kidney of rats was much higher than that in the plasma. On the contrary, in dogs, the concentration of [(14)C]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 [(14)C]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.
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Fumihiro
F
Jinno
Toshiyuki
T
Takeuchi
Yoshihiko
Y
Tagawa
Takahiro
T
Kondo
Tomoo
T
Itoh
Satoru
S
Asahi
D000814:Aniline Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001557:Benzenesulfonates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D011339:Probenecid / Q000097:blood / Q000493:pharmacokinetics; D011485:Protein Binding; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013449:Sulfonamides / Q000378:metabolism*; D014018:Tissue Distribution
C574025:4-amino-3-chlorophenyl hydrogen sulfate; D000814:Aniline Compounds; D001557:Benzenesulfonates; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D013449:Sulfonamides; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D011339:Probenecid