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Effects of PALA on the pharmacokinetics of 5-fluorouracil.

N-(phosphonacetyl)-L-aspartate (PALA) modulates the activity of 5-fluorouracil (5-FU) by inhibiting pyrimidine biosynthesis. A cross-over study was conducted to determine whether PALA affects the pharmacokinetic parameters of 5-FU in patients given 5-FU/folinic acid (FA). Six patients (3 males, 3 females) aged 63 4.3 (mean SD) years (body surface area of 1.84 18 m2) with metastatic colorectal carcinoma were given two courses of treatment. The treatment consisted of 250 mg/m2 of PALA on day 1 followed by 20 mg/m2 FA and 400 mg/m2 5-FU (5 min i.v. bolus injection) on days 2-5 in one cycle of treatment (PALA+). In another treatment cycle, these doses of 5-FU and FA were given for all 5 days without PALA (PALA-). The two courses were given four weeks apart. It was determined by random selection whether the course with PALA was given before or after the course without PALA. Blood samples were collected over a period of three hours, starting from the beginning of 5-FU infusion on days 2 and 5 of both courses. Plasma concentrations of 5-FU were determined by an HPLC technique. Pharmacokinetic parameters were calculated using a non-compartmental model. While there were no significant differences between pharmacokinetic parameters in the PALA+ vs PALA- courses, there was a trend towards a decreasing area under the curve (AUC) and increasing clearance (Cl) in PALA+ courses of treatment.