银屑病患者在治疗初期低剂量甲氨蝶呤的药代动力学

Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the early period of treatment.

作者信息

Chládek J, Martínková J, Simková M, Vanecková J, Koudelková V, Nozicková M

机构信息

Department of Pharmacology, Charles University, Faculty of Medicine, Hradec Králové, Czech Republic.

出版信息

Eur J Clin Pharmacol. 1998 Feb;53(6):437-44. doi: 10.1007/s002280050404.

DOI:10.1007/s002280050404

PMID:9551702

Abstract

OBJECTIVE

The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months) after the start of antipsoriatic therapy.

METHODS

Ten male and female psoriatic patients who failed to respond to previous conventional therapy were treated with 15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the same occasions, MTX accumulation in erythrocytes obtained before MTX administration was investigated. Pharmacodynamics of MTX were evaluated using the psoriasis area and severity index (PASI) score.

RESULTS

There were marked intersubject differences (range of coefficients of variation 34.9-76.3%) in the area under the curve (AUC), peak concentration (Cmax) and clearance (CL) of MTX. Total CL was proportional to renal clearance (CLR) (r2 = 0.735, P < 0.0001) which accounted for 73 (19)% of the former. There was a strong linear relationship (r2 = 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of drug administration, the urinary excretion of MTX was 46-99% of the dose, while that of 7-OH MTX was 1.5-8.6%. In 8 of 10 patients, more than 70% of the MTX dose was recovered. No intraindividual variations of MTX kinetic parameters during treatment were observed. MTX concentrations in erythrocytes reached the steady-state concentration in the range 40.7-170 nmol.l(-1) after 2 months of therapy. Pharmacodynamic measurement versus pharmacokinetics revealed a significant inverse relationship between PASI score and MTX AUC (rs = -0.912, P < 0.002) and between PASI score and erythrocytic MTX (rs = -0.988, P < 0.002).

CONCLUSION

The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration.

摘要

目的

本研究旨在调查抗银屑病治疗开始后早期阶段（3个月）低剂量甲氨蝶呤（MTX）的药代动力学和药效学。

方法

10例对先前常规治疗无反应的银屑病患者，每周口服15mg MTX一次。在第1、5和13剂（分别对应I、II和III期）给药后，研究MTX在血浆中的药代动力学以及MTX和7-羟基甲氨蝶呤（7-OH MTX）的尿排泄情况。在相同时间点，研究给药前获取的红细胞中MTX的蓄积情况。使用银屑病面积和严重程度指数（PASI）评分评估MTX的药效学。

结果

MTX的曲线下面积（AUC）、峰浓度（Cmax）和清除率（CL）存在显著的个体间差异（变异系数范围为34.9 - 76.3%）。总CL与肾清除率（CLR）成比例（r2 = 0.735，P < 0.0001），肾清除率占总CL的73（19）%。MTX的CL与肌酐清除率之间存在强线性关系（r2 = 0.819，P < 0.0001）。给药后48小时内，MTX的尿排泄量为剂量的46 - 99%，而7-OH MTX的尿排泄量为1.5 - 8.6%。10例患者中有8例，MTX剂量的回收率超过70%。治疗期间未观察到MTX动力学参数的个体内变异。治疗2个月后，红细胞中的MTX浓度达到稳态浓度，范围为40.7 - 170 nmol·l(-1)。药效学测量与药代动力学对比显示，PASI评分与MTX AUC之间存在显著负相关（rs = -0.912，P < 0.002），PASI评分与红细胞MTX之间也存在显著负相关（rs = -0.988，P < 0.002）。