Stereoselective glucuronidation of carvedilol in human liver and intestinal microsomes.
OBJECTIVE
Carvedilol is used clinically as a β-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.


CONCLUSIONS
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.
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. nhanioka@cc.okayama-u.ac.jp
Nobumitsu
N
Hanioka
Sawako
S
Tanaka
Yushi
Y
Moriguchi
Shizuo
S
Narimatsu
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism*; D000077261:Carvedilol; D002851:Chromatography, High Pressure Liquid; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D020719:Glucuronides; D011412:Propanolamines; D012333:RNA, Messenger; D000077261:Carvedilol; D014453:Glucuronosyltransferase