Clinical Pharmacokinetics of High-Dose Leucovorin Calcium After Intravenous and Oral Administration

Publisher Website
Google Scholar
Abstract
The clinical formulation of leucovorin calcium (leucovorin, LV) is a mixture of stereoisomers [(6R,S)-5-formyltetrahydrofolate], which have been shown to differ significantly in plasma clearance and route of elimination after intravenous administration; the (6S) isomer is rapidly converted to 5-CH 3 tetrahydrofolate (5-CH 3 (5-CH 3 THF, and the (6R) isomer is slowly eliminated by renal excretion. The relative importance of (6S) LV and 5-CH 3 THF in expanding reduced folate pools in tumor cells is unknown, but it is known that high concentrations of (6R) LV can support growth of folatedepleted cells and thus have the potential to interfere with the biological activity of the (6S) isomer. To examine the pharmacokinetics of the LV isomers and metabolites, we administered 1,000 mg of LV to five normal subjects as a 2-hour intravenous infusion and in divided oral 100-mg doses given over 24 hours. Plasma and urine samples were analyzed by reverse phase followed by chiral high-performance liquid chromatography. Following intravenous administration, peak plasma concentrations of (6R) LV, (6S) LV, and 5-CH 3 THF were 148 ± 32, 59.1 ± 22, and 17.8 ± 17 μ M , respectively. During oral administration of LV, virtually no (6S) LV appeared in the plasma. Steady-state plasma concentrations of (6R) LV and 5-CH 3 THF were approximately 1.5 ± 0.23 and 2.8 ± 0.41 μM, respectively. Intravenous administration of LV resulted in an area under the curve (AUC) for (6R) LV that was more than four times that of the biologically active (6S) folates, whereas oral administration produced an AUC for (6S) reduced folates [(6S) LV and 5-CH 3 THF] that was approximately twice that of (6R) LV. After administration of high doses of LV intravenously, conversion of (6S) LV to 5-CH 3 THF was saturable, as indicated by the prolonged (6S) LV halflife of 58 minutes and the slow (6S) LV clearance of 119.2 ± 38 mL/min, compared with previously reported data for administration of low doses. This study illustrates that intravenous administration of LV produces equivalent AUCs of (6S) LV and 5-CH 3 THF but a substantially higher AUC for (6R) LV. Oral administration over 24 hours restults in an AUC of 5-CH 3 THF equivalent to that obtained after intravenous dosing in the presence of only small amounts of (6R) LV. The optimal route of LV administration will ultimately be determined by ongoing studies of the cellular pharmacology of LV that will determine if high concentrations of (6R) LV interfere with the biological activity of the (6S) reduced folates. [J Natl Cancer Inst 82:1411–1415, 1990]