Kovarik J M, Mueller E A, Gaber M, Johnston A, Jähnchen E
Department of Human Pharmacology, Sandoz Pharma, Ltd., Basle, Switzerland.
J Clin Pharmacol. 1993 Jun;33(6):513-21. doi: 10.1002/j.1552-4604.1993.tb04697.x.
Anecdotal reports from clinical trials assessing the use of cyclosporine in the treatment of rheumatoid arthritis suggest an association between enhanced renal impairment and combined use of cyclosporine with nonsteroidal anti-inflammatory drugs. To explore possible pharmacokinetic contributions to this phenomenon, a randomized, two-period crossover investigation was performed in 24 healthy volunteers in which a single oral dose of 300 mg cyclosporine was administered alone and on day 10 of multiple oral dosing of aspirin 960 mg three times daily. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a steady-state dosing interval for aspirin on day 9 (aspirin alone) and day 10 (coadministration of cyclosporine and aspirin). Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay and plasma concentrations of acetylsalicylic acid and metabolites by high-performance liquid chromatography. Lack of a pharmacokinetic interaction was conclusively demonstrated for the rate and extent of cyclosporine and acetylsalicylic acid absorption and for the rate and extent of salicylic acid formation after a single dose of cyclosporine was coadministered during steady-state aspirin dosing. If a clear association between enhanced renal impairment and the combined use of cyclosporine and aspirin is substantiated, the underlying mechanism appears to be pharmacodynamic rather than pharmacokinetic.
评估环孢素用于治疗类风湿性关节炎的临床试验的轶事报告表明，肾功能损害加重与环孢素和非甾体抗炎药联合使用之间存在关联。为了探究这一现象可能的药代动力学因素，对24名健康志愿者进行了一项随机、两阶段交叉研究，在该研究中，单独给予单次口服剂量300毫克环孢素，并在每日三次口服960毫克阿司匹林多剂量给药的第10天给予该剂量。在每次环孢素给药后48小时内以及第9天（仅服用阿司匹林）和第10天（环孢素与阿司匹林合用）阿司匹林的稳态给药间隔期间采集系列血样。通过特异性单克隆放射免疫测定法测定环孢素全血浓度，通过高效液相色谱法测定乙酰水杨酸及其代谢产物的血浆浓度。在稳态阿司匹林给药期间合用单次剂量环孢素后，环孢素和乙酰水杨酸的吸收速率和程度以及水杨酸形成的速率和程度均未发现药代动力学相互作用。如果肾功能损害加重与环孢素和阿司匹林联合使用之间的明确关联得到证实，其潜在机制似乎是药效学而非药代动力学的。
