Entero-hepatic cycling of methotrexate estimated by use of the D-isomer as a reference marker

Summary

The absorption and elimination kinetics of 4-amino-N10-methylpteroyl-D-glutamic acid (D-MTX), the optical isomer of methotrexate (L-MTX), were examined. Test doses of 10 mg D-MTX were administered i.v. and orally to nine patients and its plasma concentration and urinary excretion were followed. The plasma curves after an i.v. bolus injection of D-MTX declined strictly biexponentially and reached zero after about 16 h. The elimination rate constants were estimated as the terminal first order rate constants. The absorption of orally administered D-MTX, estimated by its 24 h urinary recovery, in all cases was less than 3% of the dose administered. The insignificant intestinal absorption made it possible to estimate the renal and biliary secretion rates of D-MTX from the overall elimination rate constant and from the fraction of the dose excreted in urine. In three of the patients, elimination rate constants both for D-MTX and L-MTX were obtained. The renal elimination rates of the two compounds were found to be nearly identical. The median ratio of biliary/renal excretion of D-MTX was 0.94 (range 0.41–1.50), which indicates extensive entero-hepatic cycling and active reabsorption of L-MTX at the therapeutic dose levels used in psoriasis.