[High-dose methotrexate and hyperphenylalaninemia]

The occurrence of increased levels of blood phenylalanine after therapeutic administration of folate analogues has been occasionally reported and attributed to the inhibition of dihydropteridine reductase, an enzyme maintaining the cofactor of phenylalanine hydroxylase in its active tetrahydrogenated form (tetrahydrobiopterin). To study further this metabolic effect, 46 patients receiving high dose methotrexate (5 to 8 g/m2) infusions have been studied. Significant increase in serum phenylalanine was observed in 95% of methotrexate cycles, occurring at the end of infusion. In contrast to the large inter-individual variations, maximal phenylalanine concentrations were of the same magnitude in each individual, suggesting individual predispositions. The hypothesis of an inhibition of dihydropteridine reductase by methotrexate was supported by the parallel course of serum biopterin and phenylalanine levels, but in some way contradicted by the rapid return to baseline values of both, 24 hours after the end of methotrexate infusion. This transient and often moderate hyperphenylalaniemia is probably harmless except if it reflects a more general inhibition of pteridine-dependent hydroxylases. Especially, such an inhibition of cerebral tyrosine- and tryptophan-hydroxylase activities might be the reason for transient neurological disturbances observed in some patients on high-dose methotrexate treatment.