EFFECT OF PROBENECID ON THE ENANTIOSELECTIVE PHARMACOKINETICS OF OXPRENOLOL AND ITS GLUCURONIDES IN THE RABBIT

Purpose. To study the effect of probenecid on the stereoselective phar macokinetics of oxprenolol and its glucuronides in the rabbit. Methods . An oral dose of 50 mg!kg racemic oxprenolol was given to nine rabbit s twice, in random sequence with and without the concurrent administra tion of probenecid. Oxprenolol enantiomers were determined in plasma a nd urine by an enantioselective HPLC method. Oxprenolol glucuronides w ere measured in plasma and urine after enzymatic hydrolysis. Results. The disposition of the oxprenolol enantiomers in rabbits is stereosele ctive, mainly due to a difference in metabolism. Renal excretion is on ly a minor elimination route for unchanged oxprenolol, and the renal c learances of the enantiomers are similar. Pretreatment with probenecid did not affect the plasma concentrations of the oxprenolol enantiomer s, but there was a slight decrease in their urinary excretion. The pla sma concentrations of the oxprenolol glucuronides are much higher than those of the parent enantiomers, and those of (S)-glucuronide are abo ut twice those of its antipode. About 10% of the oxprenolol dose is ex creted in the urine as glucuronides. The renal clearances of both gluc uronides are similar, and markedly higher than the creatinine clearanc e. After probenecid, the mean glucuronide plasma levels were markedly higher, with for both glucuronides a more than twofold increase in mea n AUC. Probenecid decreased the renal clearance of both glucuronides t o about 30%. Moreover, it decreased slightly the formation clearance o f (S)-glucuronide, while the formation clearance of (R)-glucuronide wa s not significantly influenced. Conclusions. Our results show that in the rabbit, both oxprenolol glucuronide diastereomers are actively sec reted by the kidney, and that this process is inhibited by probenecid.