Sperschneider H, Wagner C, Korn A, Christians U
Klinik für Innere Medizin IV, Friedrich-Schiller-Universität Jena.
Med Klin (Munich). 1997 Oct 15;92(10):589-96. doi: 10.1007/BF03044784.
Diltiazem reduces the cyclosporine dose required for blood levels in the therapeutic target range by 30 to 40%. The effect of diltiazem on the pharmacokinetic disposition of cyclosporine after oral Neoral application is unknown and it is unclear whether or not the diltiazem-cyclosporine interaction is affected by the galenic cyclosporine formulation.
Fifty-one stable renal allograft patients (19 females, 32 males) were enrolled in this prospective, randomized and double-blind study. The patients were assigned to 3 treatment groups: with diltiazem (I, n = 17), with nifedipine (II, n = 17) and without calcium channel blockers (III, n = 17). Nine patients in each group received Sandimmun and 8 patients Neoral. Blood concentrations of cyclosporine and its metabolites AM1 and AM9 were measured using HPLC for 12 weeks. The 3 treatment groups were not different in respect to age, gender distribution and serum creatinine concentration. Cyclosporine doses were adjusted on basis of the blood levels.
The cyclosporine doses required to achieve target blood levels were significantly lower in group I compared with group II (-43%) and group III (-33%; p < 0.0001). Although the cyclosporine blood concentrations in all groups were in the therapeutic range, the blood levels in group I showed a much lower variability. The blood concentrations of the metabolite AM1 in group I were significantly higher than those in groups II and III after dose correction (p < 0.0001), those of AM9 were significantly lower in group I than in groups II and III (p < 0.0001). The average dose, and the blood concentration of cyclosporine was not different when patients receiving Neoral were compared with those receiving Sandimmun within the groups. In the patients in group I, the blood concentration of metabolite AM1 was significantly higher after Sandimmun application than after Neoral. No other differences in the metabolite concentrations were detected within the groups comparing patients taking Sandimmun or Neoral. The incidences of acute rejection were lower in group I (17.6%) than in the other groups (II: 52.9%; III: 41%).
Diltiazem significantly reduced the necessary dose of cyclosporine. Compared with groups II and III, the blood concentrations were more stable in patients in group I. Diltiazem increased the blood concentration of AM1 in patients treated with Sandimmun to a larger extent than in patients taking Neoral. No additional pharmacokinetic differences of the 2 cyclosporine applications different with Sandimmun or Neoral were found.
地尔硫䓬可使维持治疗目标范围内血药浓度所需的环孢素剂量降低30%至40%。口服新山地明后，地尔硫䓬对环孢素药代动力学处置的影响尚不清楚，且地尔硫䓬与环孢素的相互作用是否受环孢素剂型的影响也不明确。
51例稳定的肾移植患者（19例女性，32例男性）纳入了这项前瞻性、随机双盲研究。患者被分为3个治疗组：地尔硫䓬组（I组，n = 17）、硝苯地平组（II组，n = 17）和无钙通道阻滞剂组（III组，n = 17）。每组9例患者服用山地明，8例患者服用新山地明。使用高效液相色谱法测定环孢素及其代谢产物AM1和AM9的血药浓度，为期12周。3个治疗组在年龄、性别分布和血清肌酐浓度方面无差异。根据血药浓度调整环孢素剂量。
与II组（-43%）和III组（-33%；p < 0.0001）相比，I组达到目标血药浓度所需的环孢素剂量显著更低。尽管所有组的环孢素血药浓度均在治疗范围内，但I组的血药浓度变异性更低。剂量校正后，I组代谢产物AM1的血药浓度显著高于II组和III组（p < 0.0001），I组AM9的血药浓度显著低于II组和III组（p < 0.0001）。各组中，服用新山地明的患者与服用山地明的患者相比，环孢素的平均剂量和血药浓度无差异。在I组患者中，服用山地明后代谢产物AM1的血药浓度显著高于服用新山地明后。在比较服用山地明或新山地明的患者的组内，未检测到代谢产物浓度的其他差异。I组急性排斥反应的发生率（17.6%）低于其他组（II组：52.9%；III组：41%）。
地尔硫䓬显著降低了环孢素的必要剂量。与II组和III组相比，I组患者的血药浓度更稳定。与服用新山地明的患者相比，地尔硫䓬使服用山地明治疗的患者的AM1血药浓度升高幅度更大。未发现山地明和新山地明这两种环孢素制剂在药代动力学上有其他差异。
