ABSTRACT
BACKGROUND AND PURPOSE: Carvedilol is used clinically as a ß-adrenoceptor antagonist for the treatment of chronic heart failure and is primarily metabolized into glucuronides by UDP-glucuronosyltransferase (UGT). In this study, the stereoselective glucuronidation of carvedilol by the human liver and intestinal microsomes was examined using racemate and enantiomers. METHODS: Carvedilol glucuronidation activities at substrate concentrations of 1-1,000 µmol/l in human liver and intestinal microsomes were determined by high-performance liquid chromatography with fluorescence detection, and the kinetic parameters were estimated. RESULTS: The activities of S-glucuronidation toward racemic and enantiomeric carvedilol in liver microsomes were higher than those of R-glucuronidation at all substrate concentrations examined. In intestinal microsomes, the activities of S-glucuronidation from racemic and enantiomeric carvedilol at ≤100 µmol/l substrates were higher than those of R-glucuronidation, whereas the glucuronidation activities at ≥200 µmol/l substrates exhibited the opposite stereoselectivity (R > S) compared with those at ≤100 µmol/l substrates. The activities of R- and S-calvedilol glucuronidation from racemate and enantiomers in the liver and intestinal microsomes were decreased at substrate concentrations of ≥100 or 200 µmol/l, and the kinetics at substrate concentrations of 1-100 and 1-1,000 µmol/l fitted with Michaelis-Menten and substrate inhibition models, respectively. The stereoselectivities of CL(int) values for carvedilol glucuronidation followed by Michaelis-Menten and substrate inhibition models were R < S for liver microsomes and R ≈ S for intestinal microsomes. CONCLUSION: These findings demonstrate that the stereoselectivity of carvedilol glucuronidation was different between human liver and intestinal microsomes, and suggest that the difference is due to the tissue-specific expression of UGT isoforms involved in the glucuronidation of carvedilol.
