Plasma kinetic study of folinic acid and 5-methyltetrahydrofolate in healthy volunteers and cancer patients by high-performance liquid chromatography |
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Authors: | Brigitte Payet Gérard Fabre Nicole Tubiana Jean-Paul Cano |
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Institution: | (1) Institut I. Paoli-J. Calmettes, INSERM U 278, 232, boulevard de Sainte Marguerite, BP 156, F-13273 Marseille Cedex 9, France;(2) Faculté de Pharmacie, 27, boulevard Jean Moulin, F-13385 Marseille Cedex 5, France |
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Abstract: | Summary A reversed-phase HPLC method is described for the simultaneous determination of folinic acid, MTX, and their plasma metabolites 5-CH3–FH4 and 7-OH-MTX respectively. In addition, this technique allows the separation of FA another naturally occurring folate, and of AMT, used as internal standard.Separation of these compounds was achieved on a Waters Spherical C18 column at a flow rate of 0.8 ml.min-1. Elution was carried out with 0.1 M sodium acetate buffer (pH 5.5) as solvent A and 7.5% acetonitrile 92.5% bidistilled water as solvent B. UV detection was performed at 280 nm. This method was applied in a pharmacokinetic study of folinic acid and its plasma metabolite 5-CH3–FH4 following two different protocols: (1) i. v. bolus injection of 50 mg calcium folinate in six healthy volunteers and (2) simultaneous i. v. bolus injections of 50 mg/m2 MTX and 50 mg/m2 folinic acid in four cancer patients. Mean apparent half-life values for folinic acid and its metabolite were 7.02±1.81 h and 3.90±0.86 respectively in the first protocol, 4.80±1.48 h and 4.74±1.47 h in the second protocol. MTX and 7-OH-MTX were also quantified in the second protocol and were found not to affect the pharmacokinetics of folinic acid and 5-CH3–FH4.Since in vitro studies on metabolism of folinic acid might be of great interest in trying to assess the mechanism of action of the folates and the potential interaction of MTX and 7-OH-MTX in this mechanism via the metabolism, the chromatographic method we describe here has been adapted for the separation of all the potential intracellular monoglutamyl metabolites of folinic acid.Abbreviations FH2
dihydrofolate
- FH4
tetrahydrofolate
- 5-CHO–FH4
5-formyltetrahydrofolate
- 10-CHO–FH4
10-formyltetrahydrofolate
- 5-CH3–FH5
5-methyltetrahydrofolate
- 5,10-CH=FH4
5,10-methenyltetrahydrofolate
- MTX
methotrexate
- 7-OH-MTX
7-hydroxymethotrexate
- AMT
aminopterin
- HPLC
high-performance liquid chromatography
This work was supported by the Fédérations Nationale et Départmentale des Centres de Lutte contre le Cancer, by the Ministère de la Recherche et de la Technologie and by the Association pour le Développement de la Recherche sur le Cancer |
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