PHARMACOKINETICS OF BECLOBRIC ACID ENANTIOMERS AND THEIR CONJUGATES AFTER SINGLE AND MULTIPLE ORAL DOSAGE OF RACEMIC BECLOBRATE

The chiral lipid regulating agent beclobrate (CAS 55937-99-0), which was marketed as racemate, is - like clofibrate - rapidly hydrolyzed to beclobric acid immediately after absorption. Pharmacokinetic data were only available for the total concentration, but not for the two enantiomers. Therefore, the pharmacokinetics of (-)- and (+)-beclobric acid were studied in 8 healthy male volunteers after a single 100 mg dose of rac-beclobrate and under steady state conditions, i.e. after repetitive dosage of 100 mg beclobrate once daily for 8 days. After oral administration unchanged beclobrate was not detected in plasma. Distinct differences were found in the pharmacokinetic parameters of the two beclobric acid enantiomers. The maximum plasma concentrations and the AUC values of the (+)-enantiomer exceeded those of the (-)-enantiomer nearly 2 fold. Beclobric acid, the active metabolite, is converted to an acyl glucuronide. The diastereomeric glucuronides were detected in the plasma of all volunteers, but the differences in the pharmacokinetics were not as evident as for beclobric acid enantiomers. A comparison of the measured steady-state beclobric acid enantiomer concentration and those simulated on the basis of the parameters (open two-compartment model) obtained for a single beclobrate dose showed that the accumulation factor is slightly but nevertheless significantly higher than predicted.