Evaluation of Effects of Polymorphism for Metabolic Enzymes on Pharmacokinetics of Carvedilol by Population Pharmacokinetic Analysis

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  • Takekuma Yoh
    Laboratory of Pharmcotherapeutic Information, Department of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University
  • Takenaka Toru
    Department of Pharmacy, Hokkaido University Hospital
  • Kiyokawa Masami
    Department of Pharmacy, Hokkaido University Hospital
  • Yamazaki Koujiro
    Department of Pharmacy, Hokkaido University Hospital
  • Okamoto Hiroshi
    Department of Cardiovascular Medicine, Hokkaido University Hospital
  • Kitabatake Akira
    Department of Cardiovascular Medicine, Hokkaido University Hospital
  • Tsutsui Hiroyuki
    Department of Cardiovascular Medicine, Hokkaido University Hospital
  • Sugawara Mitsuru
    Department of Pharmacy, Hokkaido University Hospital

書誌事項

公開日
2007
DOI
  • 10.1248/bpb.30.537
公開者
公益社団法人 日本薬学会

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説明

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%.

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