大鼠静脉输注后脑C6胶质瘤细胞外液中氨甲蝶呤的药代动力学

Pharmacokinetics of methotrexate in the extracellular fluid of brain C6-glioma after intravenous infusion in rats.

作者信息

Dukic S, Heurtaux T, Kaltenbach M L, Hoizey G, Lallemand A, Gourdier B, Vistelle R

机构信息

Laboratoire de Pharmacologie et de Pharmacocinétique, U.F.R. de Pharmacie, Université de Reims Champagne Ardenne, Reims, France.

出版信息

Pharm Res. 1999 Aug;16(8):1219-25. doi: 10.1023/a:1018945529611.

DOI:10.1023/a:1018945529611

PMID:10468023

Abstract

PURPOSE

Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats.

METHODS

Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay.

RESULTS

Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 +/- 5.3%. MTX concentrations in tumor ECF represented about 1-2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2alpha, t1/2beta, MRT, fb, Vd, and CL(T)), except for a 1.7-fold increase of AUC(Plasma) and a 3.8-fold increase in AUC(ECF), which resulted in a 2.3-fold increase in penetration (AUC(ECF)/AUC(Plasma)). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters.

CONCLUSIONS

High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.

摘要

目的

建立甲氨蝶呤（MTX）在大鼠脑C6胶质瘤细胞外液（ECF）中的药代动力学特征。

方法

静脉输注MTX（50或100mg/kg）4小时后，连续采集血浆样本和ECF透析液。采用高效液相色谱法测定。

结果

组织学研究显示，大多数动物存在炎症、水肿、坏死和出血。体内回收率（反向透析）为10.8±5.3%。肿瘤ECF中的MTX浓度约为血浆浓度的1-2%。脑肿瘤ECF和血浆中的MTX水平迅速达到平衡。输注结束时（4小时），ECF浓度几乎达到稳态，然后与血浆浓度平行下降。剂量加倍并未改变MTX的药代动力学参数（t1/2α、t1/2β、MRT、fb、Vd和CL(T)），但AUC（血浆）增加了1.7倍，AUC（ECF）增加了3.8倍，导致渗透增加了2.3倍（AUC（ECF）/AUC（血浆））。尽管个体间存在重要差异，但根据平均药代动力学参数可以建立血浆和肿瘤ECF中MTX浓度之间的关系。