Stereoselective pharmacokinetics of a novel uricosuric antihypertensive diuretic in rats: pharmacokinetic interaction between enantiomers.
5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (DBCA), a promising uricosuric, diuretic, and antihypertensive agent, was administered intravenously to rats. The levels of DBCA in plasma and the areas under the curve of concentration versus time (AUC values) of the S(-)-enantiomer were higher than those of the R(+)-enantiomer. Total body clearance was significantly greater for the R(+)-enantiomer. This stereoselective elimination was due to a difference in the nonrenal clearance, which seemed to reflect hepatic metabolism or biliary excretion. Hepatic metabolism seemed more likely because AUC and the amount of urinary excretion of the N-monodemethylated metabolite of DBCA were greater for the R(+)-enantiomer. The plasma had higher free fractions of the S(-)-enantiomer, a result suggesting that this enantiomer is distributed more readily to the tissues, including the liver. This result indicates that protein binding was not responsible for the stereoselective metabolism of (R)-(+)-DBCA. Although there was no difference in the renal clearances of the enantiomers, the renal clearance of free (R)-(+)-DBCA exceeded that of the S(-)-enantiomer, a result indicating the preferential excretion of the R(+)-enantiomer into the urine. Comparison of the pharmacokinetics of individual enantiomers after intravenous administration of each enantiomer or its racemate showed that the enantiomers interact with one another; dosing with racemate delayed the elimination of each enantiomer because of mutual inhibition of hepatic metabolism and renal excretion for (R)-(+)-DBCA and of renal excretion for (S)-(-)-DBCA.
Higaki
K
K
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Company, Ltd., Osaka, Japan.
Kadono
K
K
Nakano
M
M
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D004232:Diuretics / Q000493:pharmacokinetics*; D004347:Drug Interactions; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013449:Sulfonamides / Q000493:pharmacokinetics*; D014528:Uricosuric Agents / Q000493:pharmacokinetics*
D000959:Antihypertensive Agents; D004232:Diuretics; D013449:Sulfonamides; D014528:Uricosuric Agents; C052960:S 8666