Effect of probenecid on the enantioselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit.
OBJECTIVE
To study the effect of probenecid on the stereoselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit.


METHODS
An oral dose of 50 mg/kg racemic oxprenolol was given to nine rabbits twice, in random sequence with and without the concurrent administration of probenecid. Oxprenolol enantiomers were determined in plasma and urine by an enantioselective HPLC method. Oxprenolol glucuronides were measured in plasma and urine after enzymatic hydrolysis.


RESULTS
The disposition of the oxprenolol enantiomers in rabbits is stereoselective, mainly due to a difference in metabolism. Renal excretion is only a minor elimination route for unchanged oxprenolol, and the renal clearances of the enantiomers are similar. Pretreatment with probenecid did not affect the plasma concentrations of the oxprenolol enantiomers, but there was a slight decrease in their urinary excretion. The plasma concentrations of the oxprenolol glucuronides are much higher than those of the parent enantiomers, and those of (S)-glucuronide are about twice those of its antipode. About 10% of the oxprenolol dose is excreted in the urine as glucuronides. The renal clearances of both glucuronides are similar, and markedly higher than the creatinine clearance. After probenecid, the mean glucuronide plasma levels were markedly higher, with for both glucuronides a more than twofold increase in mean AUC. Probenecid decreased the renal clearance of both glucuronides to about 30%. Moreover, it decreased slightly the formation clearance of (S)-glucuronide, while the formation clearance of (R)-glucuronide was not significantly influenced.


CONCLUSIONS
Our results show that in the rabbit, both oxprenolol glucuronide diastereomers are actively secreted by the kidney, and that this process is inhibited by probenecid.
Laethem
M E
ME
Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.
Belpaire
F M
FM
Wijnant
P
P
Bogaert
M G
MG
D000818:Animals; D005965:Glucuronates / Q000493:pharmacokinetics*; D008297:Male; D010096:Oxprenolol / Q000493:pharmacokinetics*; D011339:Probenecid / Q000494:pharmacology*; D011817:Rabbits; D013997:Time Factors
D005965:Glucuronates; D010096:Oxprenolol; D011339:Probenecid