STEREOSELECTIVE PHARMACOKINETICS OF OXPRENOLOL AND ITS GLUCURONIDES IN HUMANS

Objective: To study the pharmacokinetics of R(+)- and S(-)-oxprenolol and their corresponding glucuronide conjugates in healthy subjects. Me thods: An oral dose of 80 mg racemic oxprenolol was given to eight mal e volunteers. Venous blood samples and urine were collected as a funct ion of time, Oxprenolol enantiomers in plasma and urine were determine d by an enantiospecific HPLC method. Oxprenolol glucuronides in plasma and urine were measured as oxprenolol equivalents after enzymatic hyd rolysis. Results: For R-oxprenolol the area under the plasma concentra tion-time curve was slightly higher (R/S ratio, 1.19) and the oral cle arance slightly lower (R/S ratio, 0.84) than those parameters for S-ox prenolol The free fraction of R-oxprenolol in plasma was 4% higher tha n 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 d ose was excreted as unchanged enantiomers in the urine. The plasma con centrations of S-oxprenolol glucuronide were more than three times hig her than those of R-oxprenolol glucuronide. Twenty-five percent of the dose of the R-enantiomer was excreted in the mine as R-oxprenolol glu curonide; 29% of the S-enantiomer dose was excreted as S-oxprenolol gl ucuronide. The renal clearance of R-oxprenolol glucuronide was, on ave rage, 172 ml/min, suggesting active tubular secretion. In contrast, th e renal clearance of S-oxprenolol glucuronide was only 49 ml/min, whic h can be explained by the plasma binding of the compound. Conclusions: Our results show small differences in disposition between R- and S-ox prenolol but a marked difference in disposition between the glucuronid es. The difference in plasma concentrations between the oxprenolol glu curonides is mainly attributable to the stereoselectivity of the renal excretion.