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Pharmacokinetics of Methotrexate in the Extracellular Fluid of Brain C6-Glioma After Intravenous Infusion in Rats

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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 (t1/2α, t1/2β, MRT, fb, Vd, and CLT), except for a 1.7-fold increase of AUCPlasma and a 3.8-fold increase in AUCECF which resulted in a 2.3-fold increase in penetration (AUCECF/AUCPlasma). 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.

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Authors and Affiliations

  1. Laboratoire de Pharmacologie et de Pharmacocinétique, U.F.R. de Pharmacie, Université de Reims Champagne Ardenne, 51096, Reims Cedex, France

    Sylvain Dukic, Tony Heurtaux, Matthieu L. Kaltenbach, Guillaume Hoizey & Richard Vistelle

  2. Laboratoire Pol Bouin, Service d'Histologie et de Cytologie, Hôpital Maison-Blanche, CHRU de Reims, Reims, France

    Aude Lallemand

  3. Laboratoire de Pharmacie Clinique, U.F.R. de Pharmacie, Université de Reims Champagne Ardenne, Reims, France

    Bertrand Gourdier

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  1. Sylvain Dukic
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Dukic, S., Heurtaux, T., Kaltenbach, M.L. et al. Pharmacokinetics of Methotrexate in the Extracellular Fluid of Brain C6-Glioma After Intravenous Infusion in Rats. Pharm Res 16, 1219–1225 (1999). https://doi.org/10.1023/A:1018945529611

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