Plasma phenylalanine: Tyrosine ratios during high‐dose methotrexate‐citrovorum “rescue”

Abstract

We have measured phenylalanine and tyrosine in the plasma of patients with osteogenic sarcoma undergoing chemotherapy with high-dose methotrexate (HDMTX) citrovorum factor rescue (CFR). During 14 treatments in six different patients, the phenylalanine to tyrosine ratio (PHE/TYR) at 21 to 38 hours was elevated over pretreatment levels. The observed increase in plasma phenylalanine is attributed to inhibition by MTX of the phenylalanine hydroxylase system of the liver, which is not folate-dependent and thus is not corrected by administration of CV. A post-infusion increase in PHE/TYR of 571% after 22 hours in one patient and of 410% after 30 hours in another were associated with marked MTX toxicity. The greatest increase in PHE/TYR seen in a patient who did not experience toxicity was was 249% in 21 hours. Thus, in this group of patients, there appears to be a correlation between evidence of clinical MTX toxicity and the magnitude of the percentage increase in PHE/TYR in the plasma, which indicates inhibition of a liver enzyme and thus reflects the intracellular concentration of MTX.

Methotrexate Induced Seizures Associated with Acute Reversible Magnetic Resonance Imaging (MRI) Changes in a Patient with Acute Lymphoblastic Leukemia

“…MTX also leads to alteration in the plasma levels of various amino acids, including an increase in the level of phenylalanine (PA) [5]. PA elevation leads to the depletion of tetrahydrobiopterin, a cofactor of tyrosine hydroxylase and tryptophan hydroxylase [6]. This leads to a decrease in the production of catecholamines and biogenic amine neurotransmitters such as homovanillic acid (HVA) and 5-Hydroxyindoleacetic acid (5-HIAA) [5] which may predispose to seizures.…”

Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high‐dose methotrexate‐citrovorum rescue

“…Patient D was studied during seven of eight treatments with HDMTX-CFR, which represented the third series of treatments this patient had received. Data in Table I show that mean pretreatment values for the ratio of FM concentrations of Phe/Tyr for this patient had changed from those reported during his first series of treatments, 5 to 6 years earlier (patient E) [2]. The general pattern of a decline after the initial peak, with a second peak at 7 1-96 hr, persisted throughout this series of treatments, as shown in Table 11.…”

“…This chemotherapy did not similarly perturb the concentrations of other plasma amino acids, as measured by standard amino acid analysis. Extension of the study revealed increases above pre-treatment values of Phe/Tyr ratios 24 hr after the beginning of the 6-hr infusion of HDMTX in each of five additional patients [2].…”

Use of the phenylalanine:tyrosine ratio to test newborns for phenylketonuria in a large public health screening programme

“…Although the focus of the programme is to screen for classic PKU, we have examined the registry of outcomes to determine if the implementation of ratio screening has aVected the number of cases classified as variant. Before implementation, an average 21 variants were logged per year (range [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. In the 12 month period following implementation of ratio screening, 12 variants were logged.…”

“…3 5-9 In the past, the phenylalanine:tyrosine ratio has been used to identify PKU carriers, [10][11][12][13][14] diVerentiate between PKU and non-PKU hyperphenylalanemia, 15 and monitor methotrexate cancer treatment. 16 …”