STEREOSELECTIVE BIOTRANSFORMATION OF CICLETANINE IN CULTURED RAT AND HUMAN HEPATOCYTES

Abstract

Cicletanine [(±)-C] is a racemic furopyridine derivative used as an antihypertensive agent. Pharmacokinetic and metabolic studies have shown that cicletanine is rapidly and almost fully metabolized into sulfo- and glucuro-conjugated metabolites. However, the stereoselective metabolism of cicletanine is not well-known in humans. In the present study, the stereoselective aspect of cicletanine metabolism was investigated in cultured hepatocytes from humans and rats. The two enantiomers of cicletanine were both strongly metabolized in rat hepatocytes. So, after 24 h of incubation, very low amounts of free cicletanine were found [1.2% for (+)-C and 2.7% for (−)-C], respectively. In addition (±)-C was mainly biotransformed into conjugated metabolites: (−)-C mainly transformed into (−)-C-glucuronide (78.3±6.4%) and (+)-C mainly into (+)-C-sulfate (87.4±3.3%). In human hepatocytes, inter-individual variations were more marked than in rat hepatocytes. In addition (±)-C biotransformation in human was lower than the one observed in rat. (−)-C enantiomer was more metabolized than (+)-C. After a 24-h incubation the percentages of free (+)-C and (−)-C were 32.3±16.4 and 8.2±10.3, respectively. On the contrary to rat hepatocytes, both cicletanine enantiomers in humans were mainly metabolized into glucuroconjugated metabolites. These results clearly demonstrated that cicletanine underwent stereospecific metabolism in both rat and human hepatocytes.