The interaction between indomethacin and probenecid; A clinical and pharmacokinetic study

Abstract

The interaction between indomethacin and probenecid has been studied in 17 patients with rheumatoid arthritis with the use of a specific gas-liquid chromatographie method for the assay of indomethacin in plasma and urine. Probenecid in a dose of 0.5 gm twice daily improved the therapeutic response to indomethacin administered in a dose of 25 mg 3 times daily for a 3-wk period. There was an increase in the mean AUC of indomethacin in plasma from 2,553 ± 213 hr ng/ml to 4,181 ± 384 hr ng/ml when probenecid was given, but there was no change in the plasma half-life of indomethacin. There was a reduction in the mean plasma clearance of indomethacinfrom 174 ± 21 m/lkg/hr to 107 ± 14 ml/kg/hr when probenecid was added to the indomethacin therapy and a decrease in the apparent volume of distributionfrom 0.927 ± 0.16 L/kg to 0.613 ± 0.13 L/kg. There was no change in the amount of free indomethacin excreted in the urine during probenecid therapy but there was a reduction in the urinary excretion of free plus glucuronide conjugate of indomethacinfrom 8,967 ± 867 µg/day to 4,760 ± 674 µg/day, with a fall in the mean renal clearance of indomethacin glucuronide from 271 ± 48 ml/min to 126 ± 57.0 ml/min. The changes in the plasma indomethacin concentration profile during probenecid therapy are due to a decrease in the nonrenal clearance of indomethacin possibly because of reduced biliary clearance.