The CMF-regimen. Modulation of cyclophosphamide uptake and clearance by methotrexate and fluorouracil

Influence of the 2 antimetabolites used in the CMF-regimen, methotrexate (MTX, M) and fluorouracil (FUra, F) on in vivo pharmacokinetics of orally administered cyclophosphamide (CY, C), were studied in WAG/Rij rats. Blood plasma concentrations of CY following oral administration were monitored in single-agent CY, in CY + MTX (CM), in CY + FUra (CF) and in CY + MTX + FUra (CMF) treatments. Each treatment group consisted of at least 10 rats. CY was determined in 50 microliters of plasma by capillary gas chromatography on the first day of chemotherapy. Statistical analysis of blood plasma concentration data revealed a significant influence of both MTX and FUra on CY input/output function (p:0.01). MTX and FUra significantly increased the area under the plasma concentration time-curve, whereas tmax was significantly prolonged in CF and CMF treatment groups (p:0.01). It is suggested that MTX and FUra interact at the site of CY pre-systemic metabolism, including first-pass metabolism, subsequently resulting in prolonged absorption.