Distribution of methotrexate between plasma and peripheral lymph in man

The distribution of methotrexate (MTX) to interstitial fluid has been studied by determination of MTX in peripheral lymph from the leg and in plasma after parenteral administration to 6 patients. Peak concentrations of MTX in lymph appear 0.5 to 3.25 h after peak concentrations in plasma. Maximal concentrations in lymph are 16 to 48% lower than in plasma. MTX concentration ratios lymph/plasma were higher than 1.0 (1.0-2.8) in 4 patients, and lower than 1.0 (0.2-0.8) in 2 patients. 12 to 34% of MTX was protein bound in lymph, but the variation in the ratio of bound to free MTX per g lymph protein was only 0.13 to 0.18. The patients with a lymph/plasma MTX ratio above 1.0 will have high and favourable MTX concentrations for distribution to tumours in peripheral tissue, while in the patients with a low ratio conditions for distribution are less favourable. The results indicate that pharmacokinetics of MTX are in accordance with a two or multicompartment model with varying distribution characteristics. The present observations indicate that distribution of MTX is blood flow limited, but the influence of permeability cannot be excluded.