Stereoselective disposition of S-8666, a novel uricosuric antihypertensive diuretic, and its N-monodemethylated metabolite in a perfused rat liver preparation. Effect of protein binding on the kinetics of S-8666.
S-8666 (5-dimethyl-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid), a novel uricosuric antihypertensive diuretic, and its N-monodemethylated metabolite (M-I) were studied in a single pass perfused rat liver preparation under constant perfusate flow (ca. 16 ml/min). During perfusion with 100 nmol/ml of racemic S-8666 not containing bovine serum albumin (BSA), the steady-state hepatic extraction ratio of R(+)-S-8666 was two times higher (0.65 +/- 0.08) than that of S(-)-S-8666 (0.34 +/- 0.08). R(+)- and S(-)-M-I in the effluent perfusate plasma accounted for 64 and 18% of the influx rate of each enantiomeric S-8666, respectively. The N-monodemethylation was found to be responsible for the hepatic extraction of S-8666 enantiomers. S(-)-S-8666 was excreted into bile at a more rapid rate than the R(+)-enantiomer. Biliary excretion of R(+)-M-I was faster than S(-)-M-I, although the excretion rates of M-I were slower than those of S-8666 for both enantiomers. The steady-state extractions of preformed R(+)- and S(-)-M-I were low and a significant difference [S(-) greater than R(+)] was observed during the perfusion of 100 nmol/ml preformed racemic M-I without BSA. Increasing the concentration of BSA in the perfusate led to decreases in the extraction ratios of S-8666 enantiomers and biliary excretion rates of all chemicals, which was due to the decreases in the free fractions of S-8666 and M-I enantiomers. The binding of S-8666 and M-I enantiomers to BSA also showed stereoselectivity [R(+) less than S(-)].(ABSTRACT TRUNCATED AT 250 WORDS)
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
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K
Higaki
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Nakano
D000818:Animals; D004232:Diuretics / Q000378:metabolism / Q000493:pharmacokinetics*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008745:Methylation; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology; D013223:Statistics as Topic; D013237:Stereoisomerism; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics*; D014528:Uricosuric Agents / Q000378:metabolism / Q000493:pharmacokinetics*
D004232:Diuretics; D013449:Sulfonamides; D014528:Uricosuric Agents; C052960:S 8666; D012710:Serum Albumin, Bovine