Comparative pharmacokinetic analysis of 5-fluorouracil and its major metabolite 5-fluoro-5,6-dihydrouracil after conventional and reduced test dose in cancer patients

The aim of this study was to investigate the clinical pharmacokinetics of 5 -fluorouracil (5-FU) and its major metabolite 5-fluoro-5,6-dihydrouracil (5 -FDHU) in 20 colorectal cancer patients given two dose levels of 5-FU, 250 and 370 mg/m(2), administered by i.v. bolus, A reverse-phase highperformanc e liquid chromatographic method was used for the simultaneous assay of 5-FU and 5-FDHU in plasma samples obtained at baseline and at multiple time poi nts from 5 min to 4 h after 5-FU bolus as well as to assess the activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cell s (PBMCs) before 5-FU dosing. Plasma pharmacokinetic parameters of patients given 250 mg/m(2) 5-FU were significantly different from those receiving 3 70 mg/m(2); main differences were observed in the trapezoidal areas under t he plasma levels-versus-time curve from t(0) to the last measurable concent ration (area under the curve, 3.77 +/- 0.21 versus 13.61 +/- 2.3 h x mu g/m l), peak plasma concentration (C-max, 18.15 +/- 1.35 versus 48.41 +/- 7.69 mu g/ml), and total body clearance (CLTB, 54.64 +/- 3.54 versus 25.43 +/- 2 .3 l/h/m(2)), Significant differences were also observed in the main pharma cokinetic parameters of 5-FDHU after 250 and 370 mg/m(2) 5-FU including the area under the curve from t(0) to 4 h (5.39 +/- 0.32 versus 8.75 +/- 1.24 h x mu g/ml), C-max (3.60 +/- 0.16 versus 5.26 +/- 0.55 mu g/ml) and time t o C-max (T-max, 0.45 +/- 0.03 versus 0.69 +/- 0.06 h), The mean DPD activit y in PBMCs in this group of patients was 205.7 +/- 36.4 pmol of 5-FDHU/min/ mg of protein and was within the normal range; however, no significant corr elations were found between 5 FU or 5-FDHU pharmacokinetic parameters at tw o dose levels and DPD activity of PBMCs. The results of the present study p rovide the first detailed comparison of the distribution of 5-FU and its ma jor metabolite 5-FDHU at the therapeutic level as well as at reduced test d ose levels to obtain pharmacokinetic data to be used as reference values fo r the identification of patients at risk of major 5-FU toxicity due to impa ired metabolism to 5-FDHU.