Abstract

1. S-Carboxymethyl-l-cysteine is a mucolytic agent used as adjunctive therapy in the treatment of respiratory disorders. Various mechanisms of action have been proposed but few studies have attempted to link the required in vitro concentrations with those achieved actually in vivo during clinical therapy.

2. The data from several published studies has been re-analysed by WinNonlin using non-compartmental analysis modelling, Phoenix modelling and Classic PK compartmental modelling for both single (500–1500 mg) and multiple oral administration of the drug.

3. Multiple dose modelling indicated maximum peak concentrations (C_max) ranging from 1.29 to 11.22 μg/ml and those at steady state (C_ss(av)) from 1.30 to 8.40 μg/ml. For the standard therapeutic regimen of 3 × 750 mg (2250 mg/day) these values were 1.29–5.22 μg/ml (C_max) and 1.30–3.50 μg/ml (C_ss(av)). No accumulation was observed.

4. Hence, only the pharmacodynamic studies reporting significant effects below c.10 μg/ml were likely to occur in vivo and these were mainly gene-related mechanisms. The majority of events, although demonstrable in vitro, required levels much greater than possible to achieve in the clinical situation.

5. Such unappreciated disregard for in vitro–in vivo ‘concentration matching’ may lead to erroneous conclusions regarding mechanisms of action for many drugs as well as for S-carboxymethyl-l-cysteine.

摘要

1. S-羧甲基-1-半胱氨酸是一种粘液溶解剂，用作治疗呼吸系统疾病的辅助疗法。已经提出了各种作用机制，但很少有研究试图将所需的体外浓度与临床治疗期间在体内实际达到的浓度联系起来。

2. WinNonlin 使用非房室分析模型、Phoenix 模型和经典 PK 房室模型重新分析了几项已发表研究的数据，用于药物的单次（500-1500 毫克）和多次口服给药。

3. 多剂量建模指示的最大峰浓度（C ^_最大值）为1.29至11.22微克/毫升和那些在稳定状态（Ç _SS（AV） ）为1.30〜8.40微克/毫升。对于3×750毫克（2250毫克/天）的标准治疗方案，这些值分别为1.29-5.22微克/毫升（ç_最大值）和1.30-3.50微克/毫升（ç _SS（AV） ）。没有观察到积累。

4. 因此，只有报告低于c .10 μg/ml 的显着影响的药效学研究才有可能在体内发生，并且这些主要是基因相关机制。大多数事件虽然可以在体外证明，但需要的水平远高于临床情况下可能达到的水平。

5. 这种对体外-体内“浓度匹配”的忽视可能会导致关于许多药物以及 S-羧甲基-l-半胱氨酸的作用机制的错误结论。