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 (CLint) 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 CLint 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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- TAK-242
- ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate, resatorvid
- HPLC
- high-performance liquid chromatography
- AUC
- area under the time-concentration curve
- GFR
- glomerular filtration rate
- OAT/Oat
- organic anion transporter
- BLM
- basolateral membrane
- CLrenal
- renal clearance.
- Received November 23, 2011.
- Accepted December 27, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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