Abstract
Monitoring the 48-hour serum methotrexate (MTX) concentration is essential for predicting and avoiding the fatal clinical toxicity after the high dose infusion. The enzyme, dihydrofolate reductase (DHFR) inhibition assay (EIA) is the most widely used method to determine the serum MTX level due to its simplicity. However, this method is affected by other substances in serum which inhibit the DHFR. In this paper, the influence of sulfamethoxazole (SMX) and trimethoprim (TMP) on the EIA was investigated. Two patients with non-Hodgkin's lymphoma who received MTX (1400 and 3000 mg/m2), SMX (40 mg/kg), and TMP (8 mg/kg) concomitantly were investigated. MTX was intravenously infused for 24 hour with citrovorum factor rescue. The serum MTX concentrations at 48 hour measured by EIA were 1.3×10-6M in Case 1, and 7.8 × 10-7 M in Case 2, which were higher than the mean +2SD of that observed at our institute. The same sample reanalyzed by HPLC revealed MTX 4.5 × 10-7 M, 7-OH-MTX 6.0 × 10-6 M, SMX 3.5 × 10-5 M, TMP 7.0 × 10-6 M in Case 1, and MTX 3.5 × 10-7 M, 7-OH-MTX 6.1 × 10-7 M, SMX 2.5 × 10-5 M, TMP 3.5 × 10-6 M in Case 2. The in vitro DHFR inhibitory activity of TMP was 14.3% of that imposed by MTX. The apparent higher result measured by EIA was considered to be due to the cross-inhibition of DHFR by TMP. For precise monitoring of the serum MTX concentrations it is important to avoid taking the TMP preparation during treatment of MTX.
