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-ALPHA

Purpose: To measure plasma 5-fluorouracil (5-FU) levels using high-per formance liquid chromatography (HPLC) and compare the findings to the tissue metabolism of 5-FU evaluated using 19F magnetic resonance spect roscopy (MRS), during a protracted venous infusion (PVI) with or witho ut interferon-alpha. Methods: Patients receiving PVI 5-FU (300 mg/m(2) /day) with or without interferon-alpha (5 x 10(6) units 3 times per we ek), had 2 weekly plasma 5-FU levels evaluated using reverse-phase ion -pairing HPLC. These samples were drawn just prior to the patient unde rgoing MRS using a 1.5T Siemens Magnetom whole body magnetic resonance system with a 16 cm surface coil placed over normal liver or metastat ic tumour. Semi-quantitated MRS values were compared with the plasma 5 -FU levels using linear regression analysis. Data were available from patients given interferon-alpha with PVI 5-FU from day 1 or at the poi nt of 5-FU refractory disease. Results: A total of 30 patients were st udied. Plasma 5-FU concentrations while on a protracted venous infusio n varied from <25 ng/ml (0.192 mu M) to 25,000 ng/ml (192 mu M). A hig h plasma 5-FU concentration was associated with an increase in patient toxicity. Patients given interferon-cr with 5-FU had higher median pl asma 5-FU levels higher than patients on 5-FU alone (6138 vs. 218 ng/m l; p = 0.03). There was no correlation between the plasma 5-FU concent ration and tumour response. A comparison of the plasma 5-FU data to th e 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 ne gative correlation with the log plasma 5-FU concentration and 5-FU liv er signal (r = -0.63; p = 0.022). The patients experiencing toxicity, in addition to having a higher plasma 5-FU concentration did not exhib it a liver 5-FU signal, while the reverse was true for those having no toxicity. Conclusions: Plasma 5-FU levels may show greater interpatie nt variation when given as a protracted venous infusion. Levels of 5-F U correlated with treatment toxicity but not with anti-tumour activity . The addition of interferon-a to 5-FU increases plasma 5-FU levels. M RS findings suggest patients with low plasma 5-FU levels have higher 5 -FU levels in normal liver tissue than in those with higher plasma lev els.