Langman L J, Shapiro A M, Lakey J R, LeGatt D F, Kneteman N M, Yatscoff R W
Department of Laboratory Medicine, University of Alberta, Edmonton, Canada.
Transplantation. 1996 Jan 15;61(1):87-92. doi: 10.1097/00007890-199601150-00018.
The combination of pharmacokinetic and pharmacodynamic (measurement of the biological effect) monitoring of immunosuppressive drugs provides a method for the optimization of drug dosing. We chose to investigate this using mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. Using an assay developed for measurement of IMPDH activity in whole blood, the concentration required for 50% inhibition of IMPDH activity was approximately 200 mg/L (58 +/- 8.3% for whole blood [n = 6] and 55 +/- 10.0% for isolated lymphocytes). To ascertain the relationship between MPA concentration and IMPDH inhibition in vivo, dogs were administered a single dose of mycophenolate mofetil, the pro-drug of MPA, at 20 or 40 mg/kg orally. Pharmacokinetic analysis revealed that the Cmax of the 40-mg/kg group was statistically greater than that of the 20-mg/kg group (P < 0.05). There were no statistical differences in the other parameters investigated (area under the curve, beta half-life, mean residence time, volume of distribution at steady state, and clearance) between the two treatment groups. The half-life was calculated at approximately 8 hr for both dose groups. There was also substantial variability among the dogs in the absorption and clearance of MPA. An inverse relationship was found between the MPA concentration and IMPDH. Maximal inhibition of IMPDH activity of 30-40% occurs approximately 2-4 hr after dosing, followed by a gradual restoration in enzyme activity. After 24 hr, there is an increase in IMPDH activity that exceeds the pre-dosing levels in some cases by 3-fold. Evaluation of the pharmacokinetic and the pharmacodynamic responses to MPA in the canine model suggests that the drug should be administered ever 8 hr to optimize its immunosuppressive efficacy. This combined approach can be used for optimization of doses of this and other immunosuppressive drugs.
免疫抑制药物的药代动力学和药效学（生物效应测量）监测相结合，为优化药物剂量提供了一种方法。我们选择使用霉酚酸（MPA）进行研究，MPA是一种免疫抑制药物，它通过抑制肌苷单磷酸脱氢酶（IMPDH）发挥作用，IMPDH是嘌呤从头生物合成中的关键酶。使用开发的用于测量全血中IMPDH活性的检测方法，抑制IMPDH活性50%所需的浓度约为200mg/L（全血为58±8.3%[n = 6]，分离淋巴细胞为55±10.0%）。为确定体内MPA浓度与IMPDH抑制之间的关系，给犬口服单剂量20或40mg/kg的MPA前体药物霉酚酸酯。药代动力学分析显示，40mg/kg组的Cmax在统计学上高于20mg/kg组（P < 0.05）。两个治疗组在其他研究参数（曲线下面积、β半衰期、平均驻留时间、稳态分布容积和清除率）方面无统计学差异。两个剂量组的半衰期计算约为8小时。犬在MPA的吸收和清除方面也存在很大差异。发现MPA浓度与IMPDH之间呈负相关。给药后约2 - 4小时，IMPDH活性最大抑制30 - 40%，随后酶活性逐渐恢复。24小时后，IMPDH活性增加，在某些情况下超过给药前水平3倍。对犬模型中MPA的药代动力学和药效学反应评估表明，该药物应每8小时给药一次以优化其免疫抑制效果。这种联合方法可用于优化该药物及其他免疫抑制药物的剂量。
