Probenecid-induced changes in the clearance of pranoprofen enantiomers.
Probenecid is known to inhibit the elimination of several acidic drugs. Its influence on the pharmacokinetics of pranoprofen was investigated in rabbit after a single intravenous injection of racemic mixture (5 mg/kg). Levels of (-)-(R)- and (+)-(S)-pranoprofen and their glucuronide (after hydrolysis with sodium hydroxide) were determined in plasma, urine, and several tissues. The plasma concentration of the (+)-(S)-isomer was higher than that of the (-)-(R)-form. Oral coadministered probenecid (100 mg/kg) resulted in an increased plasma concentration of both enantiomers. Probenecid reduced the apparent total clearance and excretion of pranoprofen enantiomers in urine. It had a slight effect on the tissue distribution of pranoprofen at the dose used, but significantly reduced the formation of glucuronide for both enantiomers to the same extent in kidney microsomes. The differences caused by probenecid were significant with respect to its ability to inhibit glucuronidation in the kidney and subsequent excretion into urine, but enantioselective effects were negligible.
Imai
Teruko
T
Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Nomura
Tadayuki
T
Otagiri
Masaki
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001578:Benzopyrans / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D004347:Drug Interactions; D020719:Glucuronides / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011339:Probenecid / Q000008:administration & dosage*; D011422:Propionates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D011817:Rabbits; D013237:Stereoisomerism; D014018:Tissue Distribution; D014528:Uricosuric Agents / Q000008:administration & dosage*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D020719:Glucuronides; D011422:Propionates; D014528:Uricosuric Agents; C043940:pyranoprofen; D011339:Probenecid