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(-) > 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(+) < S(-)]. Although the appearance of M-I enantiomers in the effluent gradually decreased with an increase of the BSA contents in the perfusate, the R(+)- to S(-)-M-I ratio of the outflux rate from the inferior vena cava increased, revealing greater stereoselectivity of S-8666 N-monodemethylation [R(+) > S(-)] with stereoselective binding to BSA.