Gumbhir-Shah K, Kellerman D J, DeGraw S, Koch P, Jusko W J
School of Pharmacy, State University of New York at Buffalo, Buffalo, New York, USA.
Pulm Pharmacol Ther. 1999;12(6):353-62. doi: 10.1006/pupt.1999.0217.
Objectives of this study were to compare the pharmacokinetics, pharmacodynamics and safety of single cumulative doses of active (R)-salbutamol given either as the single enantiomer or racemic mixture by inhalation to subjects with mild to moderate asthma. This was a double-blind, crossover, cumulative-dose, randomized study where all subjects received either four doses of 1.25 mg of (R)-salbutamol or 2.5 mg of racemic (RS-) salbutamol by nebulization. The pharmacokinetic parameters were determined by noncompartmental analysis and model-fitting. Changes in FEV(1), plasma potassium, plasma glucose, heart rate, and QTc interval were measured. The potassium and glucose data were fitted to indirect response pharmacodynamic models. The heart rate and QTc data were evaluated using data descriptors. No significant differences in pharmacokinetics of (R)-salbutamol given as either (R)- or (RS)-salbutamol were found with AUC values of 11.90 +/- 4.37 and 11. 47 +/- 2.88 ng.h/ml. The t(max)of about 2 h reflected serial dosing rather than delayed absorption. The t(1/2)averaged about 3.5 h. The (S)-salbutamol showed AUC of 48.46 +/- 12.11 ng.h/ml with a t(1/2)of about 5 h. The changes in FEV(1)reached a plateau after an initial increase and did not return to pre-drug values for 10 h. All pharmacodynamic parameters were similar whether (R)- or (RS)-salbutamol was given. The exposure to (R)-salbutamol was identical after inhalation of (R) -and (RS)-salbutamol by subjects with asthma. Several pharmacological responses including FEV(1)were also similar and there were no unique safety concerns with either treatment.
本研究的目的是比较单次累积剂量的活性（R）-沙丁胺醇以单一对映体或外消旋混合物形式通过吸入给予轻至中度哮喘患者时的药代动力学、药效学和安全性。这是一项双盲、交叉、累积剂量、随机研究，所有受试者通过雾化吸入接受四剂1.25mg的（R）-沙丁胺醇或2.5mg的外消旋（RS）-沙丁胺醇。通过非房室分析和模型拟合确定药代动力学参数。测量第一秒用力呼气容积（FEV₁）、血浆钾、血浆葡萄糖、心率和QTc间期的变化。钾和葡萄糖数据拟合至间接反应药效学模型。心率和QTc数据使用数据描述符进行评估。以（R）-或（RS）-沙丁胺醇形式给予的（R）-沙丁胺醇的药代动力学无显著差异，AUC值分别为11.90±4.37和11.47±2.88ng·h/ml。约2小时的达峰时间（tmax）反映了连续给药而非吸收延迟。半衰期（t₁/₂）平均约为3.5小时。（S）-沙丁胺醇的AUC为48.46±12.11ng·h/ml，t₁/₂约为5小时。FEV₁在初始增加后达到平台期，10小时内未恢复到给药前值。无论给予（R）-还是（RS）-沙丁胺醇，所有药效学参数均相似。哮喘患者吸入（R）-和（RS）-沙丁胺醇后，（R）-沙丁胺醇的暴露量相同。包括FEV₁在内的几种药理反应也相似，两种治疗均无独特的安全问题。
