title: Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol.
abstract: 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.
authors.affiliation: Department of Clinical Pharmaceutics and Therapeutics, Graduate School of Pharmaceutical Science, Hokkaido University, Sapporo, Japan. y-kuma@pharm.hokudai.ac.jp
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takekuma
authors.forename: Toru
authors.initials: T
authors.lastname: Takenaka
authors.forename: Masami
authors.initials: M
authors.lastname: Kiyokawa
authors.forename: Koujiro
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Kitabatake
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sugawara
mesh_terms: 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
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6; D014453:Glucuronosyltransferase; D011412:Propanolamines; D000099148:UGT1A1 Enzyme