吸烟行为会调节口服氯吡格雷的药代动力学。

Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel.

作者信息

Yousef A-M, Arafat T, Bulatova N R, Al-Zumyli R

机构信息

Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman, Jordan.

出版信息

J Clin Pharm Ther. 2008 Aug;33(4):439-49. doi: 10.1111/j.1365-2710.2008.00936.x.

DOI:10.1111/j.1365-2710.2008.00936.x

PMID:18613862

Abstract

BACKGROUND AND OBJECTIVES

Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter-individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel.

METHODS

Seventy-six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non-compartmental analysis was used to determine peak plasma concentration (C(max)), time to peak plasma concentration (T(max)), elimination half-life (t(1/2e)), and area under the curve (AUC(0-->infinity)).

RESULTS

One-third of volunteers were smokers (n = 27) and one-half had abnormal body weight (n = 39). Smokers had lower AUC(0-->infinity) (smokers: 6.24 +/- 2.32 microg/h/mL vs. non-smokers: 8.93 +/- 3.80 microg/h/mL, P < 0.001) and shorter half-life (smokers: 5.46 +/- 2.99 vs. non-smokers: 8.43 +/- 4.26, P = 0.001). Smoking behaviour had no influence on C(max) (P = 0.3) and T(max) (P = 0.7). There was no statistically significant difference in C(max), AUC(0-->infinity), T(max) and t(1/2e) between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean +/- SE; 26.93 +/- 0.16 vs. 23.11 +/- 0.27). In general, the pharmacokinetic parameters were characterized by considerable inter-individual differences (C(max) = 3.09 +/- 0.99 microg/mL, CV = 32%), (T(max) =0.76 +/- 0.24 h, CV = 31.6%), (AUC(0-->infinity) = 7.98 +/- 3.58 microg/h/mL, CV = 44.8%), and (t(1/2e) = 7.38 +/- 4.10 h, CV = 55.6%).

CONCLUSION

Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking-cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.

摘要

背景与目的

氯吡格雷是一种重要的抗血小板药物，对预防血栓形成有效，尤其适用于接受经皮冠状动脉介入治疗的患者。氯吡格雷的治疗效果因个体间血小板抑制的异质性而受限，这可能归因于已知的氯吡格雷药代动力学变异性。本研究的目的是评估吸烟和体重异常对氯吡格雷药代动力学的影响。

方法

随机选择76名健康成年男性志愿者。每位受试者在禁食过夜后口服75mg单剂量氯吡格雷。测量血浆中氯吡格雷羧酸水平，并采用非房室分析来确定血浆峰浓度（C(max)）、达峰时间（T(max)）、消除半衰期（t(1/2e)）和曲线下面积（AUC(0→∞)）。

结果

三分之一的志愿者吸烟（n = 27），一半体重异常（n = 39）。吸烟者的AUC(0→∞)较低（吸烟者：6.24±2.32μg/h/mL，非吸烟者：8.93±3.80μg/h/mL，P < 0.001），半衰期较短（吸烟者：5.46±2.99，非吸烟者：8.43±4.26，P = 0.001）。吸烟行为对C(max)（P = 0.3）和T(max)（P = 0.7）无影响。体重异常和体重正常的志愿者在C(max)、AUC(0→∞)、T(max)和t(1/2e)方面无统计学显著差异。然而，两组体重差异相对较小（均值±标准误；26.93±0.16 vs. 23.11±0.27）。总体而言，药代动力学参数个体间差异较大（C(max)=3.09±0.99μg/mL，CV = 32%），（T(max)=0.76±0.24h，CV = 31.6%），（AUC(0→∞)=7.98±3.58μg/h/mL，CV = 44.8%），（t(1/2e)=7.38±4.10h，CV = 55.6%）。