The effect of malignant disease on the metabolism of pteroylglutamic acid in man.

The metabolism of Pte-Glu* has been extensively studied in rats and a breakdown process demonstrated (Murphy et al., 1976; Connor et al., 1979). However, previous studies in human volunteers have produced incomplete, conflicting results. In the present study the metabolism of PteGlu was investigated in hospital in-patients, who gave their informed consent. Patients with malignant disease were compared with a control group suffering from other disorders. Fourteen patients were given an oral dose of a mixture of [2-"C]and [3',5',7,9-3H]-PteGIu (0.5, 1.0 or 5.0mg of PteGlu). Urine was collected on to sodium ascorbate for the following time periods: 0-6h, 6-12h and 12-24h after administration. In some cases, faeces were collected for 0-48 h. Total radioactivity in urine and faeces was determined as described previously (Barford et al., 1978; Connor et al., 1979). Urine samples were sequentially chromatographed on DEAEcellulose. Sephadex G-15 and paper (Barford et al., 1977; Connor et al., 1979). In all cases this revealed a number of radioactive components and the following metabolites were identified by co-chromatography with authentic standards; PteGlu, 5 -methyltetrahydropteroylglutamate, 10formylpteroylglutamate, p-acetamidobenzoyl-L-glutamate and p-acetamidobenzoate. 'H,O and at least one species labelled Abbreviation: PteGlu, pteroylglutamic acid. principally with I4C were also detected. At the 5mg dose, quantitative analysis shows some differences between patients suffering from malignancies and control subjects, 34.0% of 3H and 28.4% of 14C and 15.9% of 'H and 13.0% of I4C of the dose being excreted in the urine in 24 h by the control subjects and cancer patients respectively. In every case an excess of 'H over I4C was observed in the urine. The urinary recovery of the individual cancer patients shows a correlation between the total urinary recovery and the size of the tumour. The urinary recovery decreased as the approximate size and extent of the tumour mass increased, indicating a larger requirement for folate in malignant disease. Up to 10.3% of 3H and 26.6% of 14C of the dose was recovered in the faeces examined, an excess of "C over .'H being present, as observed in the rat (Pheasant 8c Blair, 1979). The relative amounts of metabolites excreted in urine is shown in Table 1. The cancer patients tended to excrete less unchanged PteGlu and the ratio between PteGlu and 5-methyltetrahydropteroylglutamate decreased considerably with time, whereas it remained relatively constant in the control group. p-Acctamidobenzoyl-L-glutamate excretion was maximal in the first time period and decreased thereafter, whereas p-acetamidobenzoate shows a reciprocal pattern. It was not present in the 0-6 h urine sample of either group, appeared in the 6-12h urine sample of the cancer patients and in the 12-24h collection in both groups. In general, the excretion of scission products relative to intact folates increased with time. Control and cancer patients receiving 1 mg of PteGlu excreted 5.3% of 3H and 3.5% of I4C and 2.5% of 3H 1.7% of I4C of the dose in the urine in 24h respectively; the values for those receiving 0.5mg of PteGlu were 3.4% of 3H and 2.3% of "C