PHARMACOKINETICS OF RAC-LEUCOVORIN VS [S]-LEUCOVORIN IN PATIENTS WITHADVANCED GASTROINTESTINAL CANCER

1 The pharmacokinetics of [R]-leucovorin ([R]-LV), [S]-leucovorin ([S] -LV) and the circulating metabolite [S]-5-methyltetrahydrofolate ([S]- 5-MTHF) were studied after administration of racemic LV and [S]-LV in 21 subjects. 2 After intravenous infusion of 600 mg m(-2) rac-LV (grou p 1, n = 7) or 300 mg m(-2) [S]-LV (group 3, n = 7), the decay of [S]- LV in plasma was biexponential with a distribution half-life of 0.8 to 1 h and an elimination half-life of 11 to 23 h. When rac-LV was admin istered as a 2 h.i.v. infusion (400 mg m(-2)) following a loading dose of 200 mg m(-2) (group 2, n = 7), the plasma concentrations of [R]-LV and [S]-5-MTHF decayed monoexponentially with mean (+/- s.d.) half-li ves of 10 +/- 3 h and 7 +/- 2 h, respectively. 3 The AUC of [S]-5-MTHF was significantly higher after infusion of 300 mg m(-2) [S]-LV than a fter infusion of 600 mg m(-2) rac-LV (83 +/- 22 mu g ml(-1) h vs 53 +/ - 22 mu g ml(-1) h; P = 0.01). 4 Intrahepatic administration of 600 mg m(-2) rac-LV via the hepatic artery resulted in a decrease in the AUC of [S]-LV (AUC: 59 +/- 9 mu g ml(-1) h vs 104 +/- 23 mu g ml(-1) h; P = 0.01) and an increase in the AUC of [R]-LV (AUC: 572 +/- 76 mu g ml (-1) h vs 427 +/- 47 mu g ml(-1) h; P = 0.01) when compared with the i ntravenous infusion, suggesting that the [R]-isomer is not biologicall y inert as described in the literature. 5 The differences in the pharm acokinetics of the physiologically active compound [S]-LV and [S]-5-MT HF after intravenous administration of [R,S]-LV or [S]-LV might influe nce the modulation of 5-fluorouracil (5-FU) activity. Extensive extrac tion of [S]-LV in the liver after intraarterial administration suggest s advantages for the regional application of LV in combination with 5- FU in patients with liver metastases only.