卡维地洛及其代谢产物在高血压合并肾功能不全患者单次及多次口服给药后的药代动力学。

The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency.

作者信息

Gehr T W, Tenero D M, Boyle D A, Qian Y, Sica D A, Shusterman N H

机构信息

Division of Clinical Pharmacology and Hypertension, and Nephrology, Virginia Commonwealth University, Medical College of Virginia, Richmond, USA.

出版信息

Eur J Clin Pharmacol. 1999 Jun;55(4):269-77. doi: 10.1007/s002280050628.

DOI:10.1007/s002280050628

PMID:10424319

Abstract

INTRODUCTION

Carvedilol, a chiral compound possessing nonselective beta- and alpha1-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar alpha1-blocking activity; only S-carvedilol possesses beta-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the dose excreted renally as unchanged drug.

METHODS

The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients with hypertension and advanced renal insufficiency not yet on dialysis [GFR < or = 30 ml x min(-1) (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Days 2 9) dosing.

RESULTS

Mean with (SD) AUC(0-24h) (ng x h x ml(-1)) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively, primarily due to higher R-carvedilol concentrations. Mean with (SD) Cmax (ng x ml(-1)) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in controls on Days 1 and 9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC(0-24h) and Cmax values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Less than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and heart rate declined in both groups to a similar degree.

CONCLUSION

Compared with controls, average AUC(0-24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing beta-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency.

摘要

引言

卡维地洛是一种具有非选择性β和α1受体阻断活性的手性化合物，用于治疗高血压和充血性心力衰竭（CHF）。卡维地洛的对映体表现出相似的α1受体阻断活性；只有S-卡维地洛具有β受体阻断活性。卡维地洛主要在肝脏代谢，经肾脏排泄的原形药物不到剂量的2%。

方法

在高血压患者（对照组；n = 13）与高血压合并晚期肾功能不全且尚未接受透析的患者[肾小球滤过率（GFR）≤30 ml·min⁻¹（慢性肾功能不全，CRI），n = 12]中，研究了卡维地洛、R-卡维地洛和S-卡维地洛在单次给药（12.5 mg，第1天）和多次给药（每天25 mg，第2至9天）后的药代动力学。

结果

卡维地洛的平均（标准差）AUC(0 - 24h)（ng·h·ml⁻¹）在CRI组第1天和第9天分别为220（120）和618（335），而对照组分别为165（83.5）和413（247），主要是由于R-卡维地洛浓度较高。卡维地洛的平均（标准差）Cmax（ng·ml⁻¹）在CRI组第1天和第9天分别为53.4（31.4）和128（63.3），而对照组分别为46.7（23.3）和104（58.9）。两组间个体AUC(0 - 24h)和Cmax值有相当大的重叠，这表明组均值存在差异。在每个研究日，两组间卡维地洛的平均末端消除半衰期无明显差异。两组中以原形卡维地洛形式经尿液排泄的剂量均不到1%。两组的血压和心率下降程度相似。

结论

与对照组相比，肾功能不全患者在研究第1天和第9天卡维地洛的平均AUC(0 - 24 h)值分别高出约40%和50%，主要是由于R-卡维地洛浓度较高，而具有β受体阻断活性的异构体S-卡维地洛浓度仅略有变化（<20%）。鉴于个体间差异较大，这些药代动力学变化较小。两组对卡维地洛的耐受性均良好。虽然本研究不能提供最终结论，但根据本研究结果，对于中度/重度肾功能不全患者，卡维地洛的给药建议无需改变。