STEREOSPECIFIC PHARMACOKINETICS OF RAC-5-METHYLTETRAHYDROFOLIC ACID IN PATIENTS WITH ADVANCED COLORECTAL-CANCER

1 The pharmacokinetics and toxicity of racemic 5-methyltetrahydrofolic (rac-5-MTHF) acid after i.v. infusion were investigated in 18 patient s with advanced colorectal cancer. Doses of 100-600 mg rac-5-MTHF/m(2) were administered over 2 h together with a bolus of 500 mg/m(2) 5-flu orouracil (5-FU) as a midpoint injection. 2 The pharmacokinetics of bo th diastereoisomers were linear in the range from 100-600 mg 5-MTHF/m( 2). Independent of the administered dose, the maximal plasma concentra tion of [R]-5-MTHF was nearly twice that of [S]-5-MTHF. The eliminatio n of [S]-5-MTHF from plasma was considerably faster than that of the [ R]-isomer (elimination half-life: 3.1 +/- 1.0 h vs 8.3 +/- 3.2 h). No metabolites were detected in plasma and in urine samples. 3 The plasma protein binding was stereoselective ([R]-5-MTHF bound: 88.2 +/- 2.7%; [S]-5-MTHF bound: 59.9 +/- 6.8%; P < 0.001), causing a significantly higher renal clearance for [S]-5-MTHF when compared with the [R]-isome r (37.5 +/- 23.7 ml min(-1) vs 12.7 +/- 11.2 ml min(-1), P < 0.001). T here was no dose dependence, but gender influenced renal clearance (CL (ren) [R]-5-MTHF: male vs female: 20.5 +/- 14.5 ml min(-1) vs 7.8 +/- 4.7 ml min(-1), P = 0.03; CL(ren) [S]-5-MTHF: male vs female: 57.2 +/- 21.7 ml min(-1) vs 25.7 +/- 16.2 ml min(-1), P = 0.006). 4 Toxic side effects of the combination 5-FU/5-MTHF were rare and generally mild, and included stomatitis, nausea/emesis, diarrhoea, anaemia, leukopenia , and thrombocytopenia. 5 In combination with 500 mg 5-FU/m(2) a singl e dose of 600 mg rac-5-MTHF/m(2) can safely be administered to patient s with colorectal cancer. A similar therapeutic benefit of 5-MTHF to f olinic acid in the biochemical modulation of 5-FU is supported by the comparison of in vitro and in vivo data.