Shibata N, Minouchi T, Yamaji A, Park K I, Inoue H, Tomoyoshi T, Sako H, Abe H, Kodama M, Nakane Y
Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan.
Biol Pharm Bull. 1995 Jan;18(1):115-21. doi: 10.1248/bpb.18.115.
To establish an optimal method for determining a cyclosporin A (CyA) regimen based on physiological changes that occur during immunosuppressive therapy, the relationship between apparent CyA body clearance (CL/f) and the CyA erythrocyte-to-plasma distribution ratio (CyA-EP) was examined using clinical time courses obtained during routine monitoring. The CyA-EP, which was calculated by a multiple regression formula using routine data, was increased during renal dysfunction involving the normal recovery phase after transplantation, during nephrotoxicity, during acute tubular necrosis, and during acute renal rejection. CyA total body clearance (CLt), calculated by multiplying CL/f and converted bioavailability, fc (which is equal to 0.009 x LD, where LD represents the CyA level in blood per dose ratio), showed hyperbolic decay with increasing CyA-EP (the mean CLt was defined as follows: CLt = 0.937/CyA-EP), whereas fc showed exponential decay with increasing CyA-EP (the mean fc was defined as follows: fc = 0.593 x exp(-0.155 x CyA-EP)). These findings suggest that total CyA body clearance and its bioavailability were suppressed during the renal dysfunction phase. Hence, the mean CL/f as a function of the CyA-EP was given by the following equation: CL/f = 1.390 x exp(0.204 x CyA-EP)/CyA-EP. Since the CyA-EP reflects a patient's disease state and alterations in the CyA pharmacokinetic profile, these model formulae should provide an adequate method for determining a CyA dosage regimen for several disease states after renal transplantation.
为了基于免疫抑制治疗期间发生的生理变化建立一种确定环孢素A（CyA）治疗方案的最佳方法，我们利用常规监测期间获得的临床时间进程，研究了表观CyA体内清除率（CL/f）与CyA红细胞与血浆分布比（CyA-EP）之间的关系。通过使用常规数据的多元回归公式计算得出的CyA-EP，在移植后正常恢复期的肾功能不全期间、肾毒性期间、急性肾小管坏死期间以及急性肾排斥反应期间均升高。通过将CL/f与转化生物利用度fc（等于0.009×LD，其中LD表示每剂量血中环孢素A水平）相乘计算得出的CyA全身清除率（CLt），随着CyA-EP的增加呈双曲线衰减（平均CLt定义如下：CLt = 0.937/CyA-EP），而fc随着CyA-EP的增加呈指数衰减（平均fc定义如下：fc = 0.593×exp(-0.155×CyA-EP)）。这些发现表明，在肾功能不全阶段，CyA的全身清除率及其生物利用度受到抑制。因此，作为CyA-EP函数的平均CL/f由以下方程给出：CL/f = 1.390×exp(0.204×CyA-EP)/CyA-EP。由于CyA-EP反映了患者的疾病状态以及CyA药代动力学特征的改变，这些模型公式应为确定肾移植后几种疾病状态的CyA给药方案提供一种合适的方法。
