Pharmacokinetics of erythrocyte methotrexate after high-dose methotrexate.

Erythrocyte methotrexate (MTX) concentrations were determined in 10 patients with metastatic osteogenic or soft tissue sarcoma after 52 cycles of high-dose methotrexate (HDMTX). In contrast to serum MTX, pharmacokinetics of erythrocyte MTX showed three distinct phases: A rapid decrease to a nadir 2-3 days after MTX was followed by a significant rise of erythrocyte MTX until days 10-14. Subsequently there was a third phase, with a definite decrease of erythrocyte MTX concentrations with half-lives of 30-40 days. Short-term repititions of HDMTX had considerable influence on the first two phases of the kinetics. Each curve surpassed that of the previous therapy, and erythrocyte MTX concentrations increased continuously to the values measured at the end of the HDMTX infusion. The following mechanisms of MTX enrichment in erythrocytes is discussed: In erythro- and normoblasts MTX is converted to polyglutamate forms, which are retained inside the cell and are probably the reason for the relatively high sensitivity to MTX. Upon resumption of erythropoiesis the release of freshly prepared erythrocytes containing MTX and predominantly MTX polyglutamates causes the renewed increase in blood MTX levels.