Pharmacokinetics and in vitro studies of l-leucovorin. Comparison with the d and d,l-leucovorin

Abstract

Background: The active isomer of leucovorin (LV), LV-6S was compared with the racemic form, LV-6R,S and the inactive form, LV-6R. Materials and methods: Pharmacokinetic studies of LV-6S and 6R,S were performed on normal volunteers and patients. Growth of Pediococcus Cerevisiae (PC), a LV- dependent strain, was measured with the 3 forms of LV. CCRF-CEM, a leukemic human cell line, was used to compare the effect of LV-6S, 6R,S and 6R on the rescue of methotrexate (MTX) and on the cytotoxicity of 5-fluorouracil (5- FU). Results: LV-6S exhibits pharmacokinetic patterns similar to those obtained with LV-6R,S whatever the route used, oral or intravenous. The growth of PC was similar with the active isomer and the racemic form while the unnatural isomer, LV-6R did not promote any growth. Cells exposed to MTX (10-7 to 10-5 M) were rescued from MTX cytotoxicity with LV-6S and LV- 6R,S at concentrations 100 and 200 fold higher, whereas LV-6R did not reverse toxic effects of MTX. An enhancement of the cytotoxicity induced by 5-FU (10-4 M) was obtained after preexposure of cells to LV-6S or LV-6R,S while LV-6R did not exhibit any synergistic effect. Conclusion: LV-6S has similar effects to LV-6R,S in vitro and in vivo but at half doses; its clinical use prevents the possible interference of the inactive isomer, especially in patients receiving high doses of LV.