Enantiomer-enantiomer interaction of a uricosuric antihypertensive diuretic (DBCA) in renal tubular secretion and stereoselective inhibition by probenecid in the cynomolgus monkey

Abstract

1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the enantiomers following intravenous injection of individual enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals.

2. Separate administration of individual enantiomers showed higher plasma concentrations of (S)(—)-DBCA than those of the antipode, at an early period after dosing. Both enantiomers disappeared rapidly from plasma with an elimination half-life (t_1/2β) of 0.35–0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(—)-enantiomer. The major portion of both enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged drug. Tubular secretion contributed significantly to the renal excretion of DBCA, because tubular secretion clearance values of unbound drug (CL_rf,s) were 14- to 29-fold greater than creatinine clearance.

3. The presence of the antipode decreased the tubular secretion clearance (CL_rf,s) value of unbound (S)(—)-enantiomer by 30%, and tended to decrease that for the unbound (R)(+)-enantiomer, although not significantly. This indicates the occurrence of enantiomer-enantiomer interaction in the process of renal tubular secretion, and the inhibition of (S)(—)-DBCA renal excretion in the presence of the antipode.

4. Probenecid treatment significantly decreased the CL_rf,s of both enantiomers, and the extent of inhibition for the (S)(—)-enantiomer (53%) was significantly higher than that for the antipode (14%). These results show that renal tubular secretion of DBCA involves an anion transport system which prefers the (S)(—)-enantiomer, and that probenecid can preferentially inhibit (S)(—)-enantiomer secretion.