title: l-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children.
abstract: BACKGROUND
  At this time, folinic acid (FA) is commercially available as the racemic mixture d,l-FA, whose biological activity is supported by natural l-FA. The administration of d,l-FA results in the accumulation of d-FA in plasma relative to the active l-FA form; in vitro studies have shown that d-FA can compete with the polyglutamation of methotrexate (MTX).
  
  
  OBJECTIVE
  Our purpose was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture d,l-FA with the pure l-FA in rescue of high-dose MTX therapy (5 g/m2) in children with acute lymphocytic leukemia (ALL).
  
  
  METHODS
  Eighteen children with ALL were entered in this trial, which was planned with a crossover design. Four cycles of MTX were administered to each patient, and rescue was achieved orally every 6 hours at a dose of 12 mg/m2 for d,l-FA and 6 mg/m2 for pure l-FA. The d,l-FA and l-FA rescues were alternated from one cycle to the next. d-FA, l-FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific high-performance liquid chromatography assay.
  
  
  RESULTS
  Considering total active folate levels (l-FA + 5-MTHF), mean residual concentrations were similar for rescue by d,l-FA and l-FA, after two and six intakes, respectively: 92 and 186 nM for d,l-FA rescue versus 100 and 184 nM for l-FA rescue. Intra-individual comparison of total active folates (l-FA + 5-MTHF) did not show any significant difference between d,l-FA rescue and l-FA rescue. After administration of d,l-FA, the accumulation of d-FA in plasma was confirmed. For both types of FA rescue, MTX terminal half-lives were identical (average value, 13.9 hours). Considering each type of toxic effect (hematologic, hepatic, renal, and digestive), there was no significant difference in the proportion of toxic cycles following l-FA rescue or d,l-FA rescue.
  
  
  CONCLUSIONS
  The administration of the pure l-FA, compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, leads to equivalent treatment tolerance, and avoids the plasma accumulation of d-FA.
authors.affiliation: Centre Antoine Lacassagne, Nice, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Etienne
authors.forename: A
authors.initials: A
authors.lastname: Thyss
authors.forename: Y
authors.initials: Y
authors.lastname: Bertrand
authors.forename: R
authors.initials: R
authors.lastname: Touraine
authors.forename: H
authors.initials: H
authors.lastname: Rubie
authors.forename: A
authors.initials: A
authors.lastname: Robert
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid / Q000097:blood*; D006801:Humans; D007223:Infant; D002955:Leucovorin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy*; D013237:Stereoisomerism
chemical_list: D005492:Folic Acid; D002955:Leucovorin; D008727:Methotrexate