Stereoselective renal tubular secretion of a new uricosuric diuretic, 6,7-dichloro-5-(N,N-dimethylsulfamoyl)-2,3-dihydro-2-benzofurancarboxyl ic acid (S-8666), in cynomolgus monkeys.
Plasma concentration-time curves and urinary excretion of individual enantiomers of unchanged S-8666 and its N-monodemethylated metabolite, M-1, in male cynomolgus monkeys were measured after oral administration of racemic S-8666 at doses of 5, 10, and 50 mg/kg and also after intravenous injection at doses of 1, 5, and 10 mg/kg. The Tmax values for individual enantiomers of S-8666 in fasted male monkeys were 30 min after oral administration. The AUC values for S(-)-S-8666 were greater than those for R(+)-S-8666 and oral dose-AUC relationships of both enantiomers showed a linearity over the dose range used. Most of the S-8666 and a trace of M-1 were excreted in the first 24-hr urine, with no evidence of stereoselectivity from the amounts excreted. Since large portions were recovered from the urine as unchanged S-8666 after intravenous injection, most excretion occurs via the kidney. The t1/2 beta values and the Vdss for S(-)-S-8666 after intravenous injection were smaller than those for R(+)-S-8666. The CLt and the CLr values decreased with increasing intravenous doses, indicating saturation at a renal excretion process at high plasma concentrations of S-8666. The CLt and CLr values for R(+)-S-8666 were greater than those for the S(-)-enantiomer. The unbound fraction of R(+)-S-8666 in plasma was significantly greater than that of S(-)-S-8666 [21.6% for R(+), 12.0% for S(-)]. Renal clearance for the unbound fraction of S(-)-S-8666 was greater than that of R(+)-S-8666, suggesting stereoselective renal tubular secretion.
Kanzakigawa Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
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Nakano
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Kawahara
D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D004232:Diuretics / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D007275:Injections, Intravenous; D007684:Kidney Tubules / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D011485:Protein Binding; D013237:Stereoisomerism; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D014528:Uricosuric Agents / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
D002250:Carbon Radioisotopes; D004232:Diuretics; D013449:Sulfonamides; D014528:Uricosuric Agents; C052960:S 8666