Ketoprofen-probenecid interaction in the rat: a probenecid concentration-dependent stereoselective process

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Chiral Drug Interactions

Background:

• Probenecid (PB) is known to interact with ketoprofen (KT), a chiral nonsteroidal anti-inflammatory drug.
• This interaction is thought to involve competition for glucuronide conjugation and subsequent excretion.
• The concentration-dependency and differential enantiomer effects of this interaction remain unclear.

Purpose of the Study:

• To investigate the concentration-dependent interaction between probenecid (PB) and ketoprofen (KT) enantiomers.
• To determine if both R-KT and S-KT are affected equally by probenecid.
• To elucidate the impact of varying PB doses on KT enantiomer plasma concentrations and excretion.

Main Methods:

• Intravenous administration of racemic ketoprofen (KT) and varying doses of probenecid (PB) to Sprague-Dawley rats.
• Measurement of intact and conjugated R-KT and S-KT, and PB in plasma and urine over 24 hours.
• Correlation analysis of plasma concentrations and AUCs of KT enantiomers with PB concentrations.

Main Results:

• Elevated plasma levels of both R-KT and S-KT were observed, with S-KT showing a significantly greater increase.
• Strong positive correlations were found between PB plasma concentrations and KT enantiomer plasma levels and AUCs.
• The S-KT/R-KT ratio in plasma AUC and urinary excretion increased progressively with higher PB doses.

Conclusions:

• The interaction between ketoprofen (KT) and probenecid (PB) in rats is demonstrably concentration-dependent.
• Probenecid significantly affects ketoprofen enantiomers, particularly S-KT, influencing their disposition.
• These findings highlight the importance of considering drug concentration in understanding chiral drug interactions and excretion patterns.