Gehr T W, Tenero D M, Boyle D A, Qian Y, Sica D A, Shusterman N H
Division of Clinical Pharmacology and Hypertension, and Nephrology, Virginia Commonwealth University, Medical College of Virginia, Richmond, USA.
Eur J Clin Pharmacol. 1999 Jun;55(4):269-77. doi: 10.1007/s002280050628.
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.
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.
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.
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.
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%。
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。
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。
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。
