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Clinical Specialist Service d'Oncologie Pédiatrique Hôpital pour Enfants de La Timone 13885 Marseille Cedex 5, France fax 33 (0) 491 386 832 nicolas.andre{at}ap-hm.fr
Clinical Specialist Centre Régional de Pharmacovigilance Hôpital Salvator Marseille
Clinical Specialist Service d'Oncologie Pédiatrique Hôpital pour Enfants de La Timone
Clinical Specialist Service de Pharmacologie Clinique Hôpital pour Enfants de La Timone
Clinical Specialist Service d'Oncologie Pédiatrique Hôpital pour Enfants de La Timone
Clinical Specialist Service d'Oncologie Pédiatrique Hôpital pour Enfants de La Timone
Professor Service d'Oncologie Pédiatrique Hôpital pour Enfants de La Timone
Published Online, August 15, 2006. www.theannals.com, DOI 10.1345/aph.1H082
Case Report. A 16-year-old girl was admitted to our department for a non-metastatic femoral osteosarcoma. Treatment was initiated according to the Société Française de lutte conte les Cancers de l'enfant et l'adolescent recommendations using high-dose methotrexate alternating with courses of etoposide plus ifosfamide. Following standard hydration and alkalinization, she received a first course of methotrexate 12 g/m2 (18 g). Antiemetic therapy with ondansetron and methylprednisolone was started concomitantly. Analgesic treatment with intravenous nalbuphine and oral dantrolene had been given for 4 and 1 days, respectively. No other medications were administered.
Routine monitoring of methotrexate with fluorescence immunopolarization assay showed high plasma concentrations (418 µmol/L) at the first dosage (24th h). The dosage was then confirmed using HPLC. Intensification of urine alkalinization and increased leucovorin salvage (100 mg/m2 every 3 h) were started immediately and dantrolene therapy was stopped. As soon as it was available, 50 units/kg of carboxypeptidase-G2 (CPDG2), a bacterial enzyme that allows hydrolysis of methotrexate to nontoxic metabolites,1 was administered at the 54th hour. A second dose was administered at the 78th hour. Despite CPDG2 administration, the threshold value (0.2 µmol/L), which determines the ending of rescue treatment, was reached only 324 hours after the start of the methotrexate infusion (Figure 1).
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Methotrexate was resumed at a lower dose (total 10 g) 3 weeks later; it was well tolerated, with a standard decrease in plasma concentrations. Limb salvage surgery was performed, which allowed for classification of the patient as a good responder, with 4% remaining viable cells. Overall, the patient received 16 additional courses of high-dose methotrexate. The patient was well, with no sign of disease 10 months after completion of treatment. Use of the Naranjo probability scale indicated a probable relationship between the methotrexate intoxication and dantrolene therapy in our patient.3
Discussion. Indeed, dantrolene and/or its metabolites could have impaired the clearance of methotrexate.4-6 Ninety percent of dantrolene is bound to serum proteins with strong affinity and, therefore, can modify methotrexate clearance.7 Moreover, 3 metabolites of dantrolene have been identified: 5-hydroxydantrolene, nitroreduced acetylated dantrolene, and 5-(p-nitrophenyl)-2-furoic acid. Nitroreduced acetylated dantrolene is not detectable in children, and furoic acid metabolism does not seem to interfere with either renal or hepatic metabolism of methotrexate; therefore, it is very unlikely that either compound is implicated in the potential interaction between methotrexate and dantrolene.5,6
On the contrary, 5-hydroxydantrolene is partially excreted renally. Thus, the interaction between dantrolene or 5-hydroxydantrolene and methotrexate may be secondary to both altered renal excretion of methotrexate and modification of binding of methotrexate to serum proteins, similar to interactions already reported with nonsteroidal antiinflammatory drugs.2
Although dantrolene has not previously been reported to alter renal elimination of methotrexate, we conclude, using the Naranjo probability scale, that dantrolene was the probable cause of this case of methotrexate intoxication. Therefore, we recommend using dantrolene with caution in patients receiving high-dose methotrexate.
References
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