Stereoselective pharmacokinetics of oxprenolol and its glucuronides in humans

Abstract

Objective: To study the pharmacokinetics of R(+)- and S(-)-oxprenolol and their corresponding glucuronide conjugates in healthy subjects.

Methods: An oral dose of 80 mg racemic oxprenolol was given to eight male volunteers. Venous blood samples and urine were collected as a function of time. Oxprenolol enantiomers in plasma and urine were determined by an enantiospecific HPLC method. Oxyprenolol glucuronides in plasma and urine were measured as oxprenolol equivalents after enzymatic hydrolysis.

Results: For R-oxprenolol the area under the plasma concentration-time curve was slightly higher (R/S ratio, 1.19) and the oral clearance slightly lower (R/S ratio, 0.84) than those parameters for S-oxprenolol. The free fraction of R-oxprenolol in plasma was 4% higher than that of S-oxprenolol. The intrinsic clearance of S-oxprenolol was 1.5 times larger than that of R-oxprenolol, and a maximum of 3% of the dose was excreted as unchanged enantiomers in the urine. The plasma concentrations of S-oxprenolol glucuronide were more than three times higher than those of R-oxprenolol glucuronide. Twenty-five percent of the dose of the R-enantiomer was excreted in the urine as R-oxprenolol glucuronide; 29% of the S-enantiomer dose was excreted as S-oxprenolol glucuronide. The renal clearance of R-oxprenolol glucuronide was, on average, 172 ml/min, suggesting active tubular secretion. In contrast, the renal clearance of S-oxprenolol glucuronide was only 49 ml/min, which can be explained by the plasma binding of the compound.

Conclusions: Our results show small differences in disposition between R- and S-oxprenolol but a marked difference in disposition between the glucuronides. The difference in plasma concentrations between the oxprenolol glucuronides is mainly attributable to the stereoselectivity of the renal excretion.