Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-α

Abstract

To measure plasma 5-fluorouracil (5-FU) levels using high-performance liquid chromatography (HPLC) and compare the findings to the tissue metabolism of 5-PU evaluated using 19F magnetic resonance spectroscopy (MRS), during a protracted venous infusion (PVI) with or without interferon-α. Patients receiving PVI 5-PU (300 mg/m²/day) with or without interferon-α (5 × 10⁶ units 3 times per week), had 2 weekly plasma 5-FU levels evaluated using reverse-phase ion-pairing HPLC. These samples were drawn just prior to the patient undergoing MRS using a 1.5T Siemens Magnetom whole body magnetic resonance system with a 16 cm surface coil placed over normal liver or metas tatic tumour. Semi-quantitated MRS values were compared with the plasma 5-FU levels using linear regression analysis. Data were available from patients given interferon-α with PVI 5-FU from day 1 or at the point of 5-FU refractory dis ease. A total of 30 patients were studied. Plasma 5-FU concentrations while on a protracted venous infusion varied from 25 ng/ml (0.192 µM) to 25,000 ng/ml (192 µM). A high plasma 5-FU concentration was associated with an increase in patient toxicity. Patients given interferon-α with 5-FU had higher median plasma 5-FU levels higher than patients on 5-FU alone (6138 vs. 218 ng/ml; p 0.03). There was no correlation between the plasma 5-FU concentration and tumour response. A comparison of the plasma 5-FU data to the MRS studies in normal liver revealed a positive correlation between plasma 5-FU and liver catabolite signal (r–0.68; p–0.016) but a negative correlation with the log plasma 5-FU concentration and 5-FU liver signal (r–0.63; p–0.022). The patients experiencing toxicity, in addition to having a higher plasma 5-FU concentration did not exhibit a liver 5-FU signal, while the reverse was true for those having no toxicity. Plasma 5-FU levels may show greater interpatient variation when given as a protracted venous infusion. Levels of 5-FU correlated with treatment toxicity but not with anti-tumour activity. The addition of interferon-α to 5-FU increases plasma 5-FU levels. MRS findings sug gest patients with low plasma 5-FU levels have higher 5-FU levels in normal liver tissue than in those with higher plasma levels.