Metabolism of the (+)-, (±)-, and (-)-Enantiomers of α-Methylfluorene-2-acetic Acid (Cicloprofen) in Rats

Abstract

1. After oral or intraperitoneal administration of (±)-[¹⁴C]cicloprofen to rats, the peak plasma concentrations of radioactivity and the areas under the plasma concentration/time curves did not increase proportionally with dose; total urinary and faecal excretions of radioactivity did increase with dose, suggesting saturation of plasma protein binding of drug and faster elimination of unbound drug at higher doses.

2. [¹⁴C]Cicloprofen and its metabolites were eliminated mainly via biliary excretion. Ratios of faecal to urinary excretion ranged from 2 to 3 and depended on dose administered.

3. Rats with cannulated bile ducts excreted the drug almost exclusively in bile, whereas intact rats excreted up to 32% of the dose in urine in 6 days, suggesting that [¹⁴C]cicloprofen or its metabolites or both undergo extensive enterohepatic recirculation in the rats.

4. The major metabolites of [¹⁴C]cicloprofen excreted in urine or bile were the 7-hydroxy-, 9-hydroxy-, 7,9-dihydroxy-, and 9-hydroxy-9-methoxy-derivatives and their glucuronide or sulphate conjugates.

5. The (+)-enantiomer of [¹⁴C]cicloprofen was hydroxylated and excreted by rats at a faster rate than its (-)-antipode; no qualitative stereoselective metabolism of the individual enantiomers of [¹⁴C]cicloprofen was observed.