We describe the case of a 35-year old male who developed acute renal failure following high dose methotrexate therapy for Burkitt's non Hodgkin lymphoma. Serum methotrexate levels reached 37 micromol/l, and remained higher than 1 micromol/l for more than a week. Folinic acid rescue was intensified to 200-400 mg intravenously every 4 hours. As methotrexate binds markedly to proteins, plasma exchange was initially chosen, 4 sessions being performed from day 2 to day 4. The methotrexate pharmacokinetic profile was not significantly modified during plasma exchange, and serum drug level was 3 micromol/l. Continuous veno-venous hemodiafiltration was therefore performed from day 5 to day 10. This procedure also seemed ineffective, with evidence of low ultrafiltrate clearance. No extrarenal toxicity was observed in our patient. Thus, conventional extrarenal procedures appear to have a limited role in the setting of overexposure to methotrexate. The use of very high doses of folinic acid in our case probably played a major role in the eventual favorable outcome.
[Show abstract][Hide abstract] ABSTRACT: Summary High-dose methotrexate is included in chemotherapy regimens used to treat a number of malignant neoplasms. Methotrexate plasma concentration is considered the best toxicity predictor. Monitoring methotrexate plasma concentrations is standard prac- tice in the identification of at-risk patients, the titration of folinic acid doses, and the establishment of corrective measures. Metho- trexate is a kidney-cleared weak acid, and renal function impair- ment may retard methotrexate clearance. A case of severe metho- trexate-induced toxicity secondary to renal failure is reported in a patient with non-Hodgkin's lymphoma receiving methotrexate at a dose of 1 g/m 2 . Corrective measures included folinic acid rescue therapy, cholestyramine resin administration, hydration and urine alkalinization, urine pH monitoring, and extracorporeal clearance techniques.
[Show abstract][Hide abstract] ABSTRACT: We examined the pharmacological role of the renal organic anion transporter OAT-K1, which localizes predominantly in the brush-border membranes of proximal straight tubules, in the urinary excretion of methotrexate and the possibility of its contribution to "folinic acid rescue." With Madin-Darby canine kidney (MDCK) cells stably transfected with OAT-K1 cDNA, OAT-K1-mediated methotrexate accumulation was inhibited in the presence of various folic acid derivatives. These derivatives included aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid (citrovorum factor, leucovorin), and folic acid with apparent inhibition constant values of 0.5, 1.2, 1.8, 8.2, and 14.1 microM, respectively. In contrast, 10 microM taurocholic acid and sulfobromophthalein did not inhibit OAT-K1-mediated methotrexate accumulation. In addition, methotrexate efflux was stimulated in the presence of inwardly directed gradients of aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid, and folic acid, but not of uric acid, taurocholic acid, and glutathione, indicating that OAT-K1-mediated methotrexate efflux is stimulated by a folic acid derivatives exchange. In conclusion, OAT-K1 was suggested to enhance the apical efflux of highly accumulated methotrexate in tubular epithelial cells and contribute at least in part to folinic acid rescue by exchanging intracellular methotrexate for extracellular folinic acid.
Journal of Pharmacology and Experimental Therapeutics 07/2000; 293(3):1034-9. · 3.97 Impact Factor
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