title: Evaluation of effects of polymorphism for metabolic enzymes on pharmacokinetics of carvedilol by population pharmacokinetic analysis.
abstract: In our previous study it was observed that the frequencies of UGT1A1*6, UGT2B7*3 and CYP2D6*10 in patients who have a low level ability of glucuronidation were significantly higher than those in patients with a high level of ability of glucuronidation. The same tendency was found in the frequency of CYP2D6*5, though there was no significant difference. The purpose of this study was to evaluate the effects of the polymorphism on pharmacokinetics of carvedilol by population pharmacokinetic analysis. Population pharmacokinetic analysis was performed using 373 plasma concentrations from 41 patients with chronic heart failure or angina pectoris. A one compartment pharmacokinetic model with first-order absorption (for oral dosing) was used to describe the concentration-versus-time data for carvedilol. We examined the effects of various clinical and genetic covariables in the regression models for clearance and volume of distribution. The results suggested that the factors of interindividual variation for carvedilol clearance were creatinine clearance and polymorphisms of UGT2B7 and CYP2D6 in the Japanese population with heart disease. It was estimated that UGT2B7*3 decreased the clearance of carvedilol by 37%, but UGT2B7*2 did not show any effect. Clearance in the patients who have intermediate activity of CYP2D6 was decreased by 39%.
authors.affiliation: Laboratory of Pharmcotherapeutic Information, Department of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, 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 / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077261:Carvedilol; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D003404:Creatinine; D019389:Cytochrome P-450 CYP2D6; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase