Clinical pharmacokinetics of fluorouracil and folinic acid

This article deals with the pharmacokinetics of fluorouracil (5-FU) and folinic acid (CHO-THF). 5-FU kinetics are characterized by short serum half-life times of 4.5 to 13 minutes. The high body clearance is mainly caused by a rapid catabolism of 5-FU to dihydrofluorouracil (FUH2), alpha-fluoro-ureidopropionic acid (FUPA), and to alpha-fluoro-beta-alanine (FBAL). Due to an incomplete hepatic extraction, systemic 5-FU levels greater than 5 microM are determined even during hepatic artery infusion. 5-FU measurements during isolated liver perfusion revealed different phases of 5-FU clearance. With higher levels (greater than 430 microM) clearance behaves in accordance with zero-order kinetics, with lower concentrations (less than 150 microM) 5-FU is cleared according to first-order kinetics. The impact of 5-FU kinetics on the treatment with 5-FU is discussed. After administration of the commercially available d,l-folinic acid (d,l-CHO-THF), the biologically inactive d-form is cleared very slowly with a median half-life of 438 +/- 63 minutes. l-CHO has short elimination half-lives of 56.5 +/- 10.5 minutes. The high body clearance of 222 +/- 27 mL/min is partially caused by metabolism to l-methyltetrahydrofolic acid (l-CH3-THF). With bolus injection of 200 mg/m2 or short-term infusion of 300 mg d,l-CHO-THF, serum levels greater than 1 microM are attained for approximately 2 to 3 hours. Total reduced l-folates (l-CHO-THF plus l-CH3-THF) are above 5 microM for at least 3 hours. Continuous infusion of CHO-THF affords steady-state levels in the micromolar range for prolonged time periods. After application of the pure l-folinic acid, mean elimination half-live and area under the curve were in the same range as after administration of the d,l-CHO-THF. Higher doses of oral d,l-folinic acid are always absorbed incompletely. Since the amount of l-CHO-THF absorbed is converted rapidly to CH3-THF, serum levels of l-CHO-THF remain always below 0.1 microM. CH3-THF steady-state levels in the micromolar range, however, are attained with different oral d,l-CHO-THF protocols.