Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol.
OBJECTIVE
It has been reported that carvedilol, which has beta-adrenergic blocking and vasodilating activities, is mainly metabolized by UDP-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B7 and CYP2D6. The aim of this study was to determine whether the activity of glucuronidation has an influence on the area under the curve (AUC) of carvedilol and whether polymorphisms in UGTs and CYP2D6 contribute to individual variation in disposition of carvedilol in Japanese.


METHODS
Plasma concentrations of carvedilol and its glucuronide were determined by reversed-phase high-performance liquid chromatography (HPLC). Genotyping of UGT1A1, UGT2B4 and UGT2B7 genes was carried out by the direct sequence method. CYP2D6 genotyping was carried out using an amplification refractory mutation system (ARMS) assay and PCR-restriction fragment length polymorphism (RFLP).


RESULTS
The level of carvedilol glucuronidation ability in the high-level AUC group was significantly lower than that in the low-level group. The frequencies of UGT1A1*6, UGT2B7*3 and CYP2D6*10 in the low level ability of glucuronidation group were significantly higher than those in the high level group, and the same tendency was found in the frequency of CYP2D6*5, though there was no significant difference.


CONCLUSIONS
Polymorphisms of UGT1A1, UGT2B7 and CYP2D6 strongly affect the pharmacokinetics and disposition of carvedilol in Japanese.
Takekuma
Yoh
Y
Department of Clinical Pharmaceutics and Therapeutics, Graduate School of Pharmaceutical Science, Hokkaido University, Sapporo, Japan. y-kuma@pharm.hokudai.ac.jp
Takenaka
Toru
T
Kiyokawa
Masami
M
Yamazaki
Koujiro
K
Okamoto
Hiroshi
H
Kitabatake
Akira
A
Tsutsui
Hiroyuki
H
Sugawara
Mitsuru
M
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002227:Carbazoles / Q000378:metabolism*; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6; D014453:Glucuronosyltransferase; D011412:Propanolamines; D000099148:UGT1A1 Enzyme