Sud K, Singh B, Krishna V S, Thennarasu K, Kohli H S, Jha V, Gupta K L, Sakhuja V
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Nephrol Dial Transplant. 1999 Jul;14(7):1698-703. doi: 10.1093/ndt/14.7.1698.
Cyclosporin (CsA) is metabolized primarily in the liver by cytochrome P-450 enzymes. Concomitant use of fluconazole can increase CsA concentrations by inhibiting this enzyme system and the effect seems to be dose dependent, with no interaction noted when fluconazole is used in a dose of 100 mg/day. Two previous investigations studying this interaction while using higher doses of fluconazole have provided inconsistent results. Recommendations advising an empirical 50% CsA dosage reduction in these patients have not been tested in a prospective trial.
We studied six renal transplant recipients on CsA immunosuppression in a prospective, unblinded, crossover trial. Baseline renal functions, CsA area under the curve (AUC), Cmax, Cmin, CsA clearance, and Tmax were compared with those 2, 4 and 7 days after starting fluconazole orally in a dose of 200 mg/day. From day 8 onwards, patients reduced CsA dose by 50% and the above parameters were repeated on day 14.
CsA AUC increased from 2887 +/- 1729 ng.h/ml on day 0 to 3842 +/- 1975 ng.h/ml on day 2 (P < 0.05), 4750 +/- 1718 ng.h/ml on day 4 (P< 0.01) and then decreased to 4052 +/- 1687 ng.h/ml on day 7 (P<0.01). Following CsA dose reduction by 50%, the mean AUC decreased significantly to 2330 +/- 1602 ng x h/ml (P<0.01). The Cmax showed a significant increase from 701 +/- 345 ng/ml on day 0 to 941 +/- 326 ng/ml (P < 0.01) on day 4 but decreased from 768 +/- 292 ng/ml on day 7 to 498 +/- 289 ng/ml on day 14, P<0.01. The mean Cmin increased from 207 +/- 138 ng/ml on day 0 to 274 +/- 168 ng/ml on day 4. No significant changes were observed in CsA clearance and Tmax. On repeated-measurement ANOVA, only the AUC and Cmax on day 4 of fluconazole were significantly higher than day 0 (P<0.001). There was a large interindividual variability in the degree of drug interaction between patients.
Fluconazole given orally in a dose of 200 mg/day is associated with significant increase in bioavailability of CsA. The maximum effect occurs on day 4 after starting fluconazole. Although repeated monitoring of CsA Cmin is convenient as opposed to repeated determination of AUC, changes in Cmin may not be sensitive enough to pick up this interaction. The increase in bioavailability of CsA is unpredictable in individual patients and all patients should be monitored with AUC near day 4 of treatment to guide CsA dosage reductions.
环孢素（CsA）主要在肝脏中由细胞色素P - 450酶代谢。氟康唑的同时使用可通过抑制该酶系统增加CsA浓度，且这种作用似乎呈剂量依赖性，当氟康唑以100mg/天的剂量使用时未观察到相互作用。此前两项使用较高剂量氟康唑研究这种相互作用的调查结果并不一致。建议在这些患者中经验性地将CsA剂量减少50%，但尚未在前瞻性试验中得到验证。
我们在一项前瞻性、非盲、交叉试验中研究了6名接受CsA免疫抑制的肾移植受者。将基线肾功能、CsA曲线下面积（AUC）、Cmax、Cmin、CsA清除率和Tmax与口服200mg/天氟康唑后第2、4和7天的相应指标进行比较。从第8天起，患者将CsA剂量减少50%，并在第14天重复上述参数测量。
CsA的AUC从第0天的2887±1729ng·h/ml增加到第2天的3842±1975ng·h/ml（P<0.05），第4天为4750±1718ng·h/ml（P<0.01），然后在第7天降至4052±1687ng·h/ml（P<0.01）。在CsA剂量减少50%后，平均AUC显著降至2330±1602ng·h/ml（P<0.01）。Cmax从第0天的701±345ng/ml显著增加到第4天的941±326ng/ml（P<0.01），但从第7天的768±292ng/ml降至第14天的498±289ng/ml，P<0.01。平均Cmin从第0天的207±138ng/ml增加到第4天的274±168ng/ml。CsA清除率和Tmax未观察到显著变化。重复测量方差分析显示，仅氟康唑治疗第4天的AUC和Cmax显著高于第0天（P<0.001）。患者之间药物相互作用的程度存在较大个体差异。
口服200mg/天的氟康唑与CsA生物利用度的显著增加相关。最大效应出现在开始使用氟康唑后的第4天。尽管与重复测定AUC相比，重复监测CsA的Cmin更方便，但Cmin的变化可能不够敏感，无法检测到这种相互作用。CsA生物利用度的增加在个体患者中是不可预测的，所有患者在治疗第4天左右均应监测AUC，以指导CsA剂量的减少。
