Kovarik J M, Mueller E A, Gerbeau C, Tarral A, Francheteau P, Guerret M
Novartis Pharma Inc., Basel, Switzerland.
J Clin Pharmacol. 1997 Apr;37(4):336-43. doi: 10.1002/j.1552-4604.1997.tb04311.x.
A series of clinical pharmacology studies was performed to screen for possible pharmacokinetic/dynamic contributions to drug interactions reported in rheumatoid arthritis patients receiving cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs). No clinically relevant pharmacokinetic changes in any of the drugs were noted when single-dose cyclosporine was coadministered during a steady-state regimen of aspirin, indomethacin, or piroxicam in healthy volunteers. Only with diclofenac was an interaction observed whereby the diclofenac area under the concentration-time curve was doubled in the presence of cyclosporine. Based on the outcomes of the screening studies, steady-state coadministration of both diclofenac and cyclosporine was assessed in rheumatoid arthritis patients, confirming the drug interaction of diclofenac with cyclosporine. Although the drug interaction was accompanied by a significant rise in serum creatinine, there was no apparent concentration-effect relationship, inasmuch as the increase in diclofenac exposure was not related to the magnitude of increase in serum creatinine. Based on the results of these five drug-drug interaction studies and the known biotransformation pathways of nonsteroidal antiinflammatory drugs, it is speculated that the pharmacokinetic interaction, which is unique to diclofenac, is caused by inhibition by cyclosporine of diclofenac's first-pass metabolism. Caution and appropriate clinical monitoring are recommended whenever cyclosporine and NSAIDs are coadministered; however, diclofenac in particular should be administered near the lower end of its therapeutic range when it is initially combined with cyclosporine in the treatment of rheumatoid arthritis.
开展了一系列临床药理学研究，以筛查接受环孢素和非甾体抗炎药（NSAIDs）的类风湿性关节炎患者中报道的药物相互作用的潜在药代动力学/药效学影响因素。在健康志愿者中，当阿司匹林、吲哚美辛或吡罗昔康的稳态给药方案中同时给予单剂量环孢素时，未观察到任何一种药物出现具有临床意义的药代动力学变化。仅在双氯芬酸的使用中观察到相互作用，即在环孢素存在的情况下，双氯芬酸的浓度-时间曲线下面积增加了一倍。基于筛查研究的结果，对类风湿性关节炎患者中双氯芬酸和环孢素的稳态联合给药进行了评估，证实了双氯芬酸与环孢素之间的药物相互作用。尽管这种药物相互作用伴随着血清肌酐的显著升高，但由于双氯芬酸暴露量的增加与血清肌酐升高的幅度无关，因此没有明显的浓度-效应关系。基于这五项药物相互作用研究的结果以及非甾体抗炎药已知的生物转化途径，推测双氯芬酸特有的药代动力学相互作用是由环孢素抑制双氯芬酸的首过代谢所致。当环孢素与NSAIDs联合使用时，建议谨慎并进行适当的临床监测；然而，在类风湿性关节炎的治疗中，当双氯芬酸最初与环孢素联合使用时，尤其应在其治疗范围的下限附近给药。
