Effect of penicillin on the renal tubular secretion of methotrexate in the monkey.

Abstract

The effect of penicillin on the renal tubular secretion of methotrexate (MTX) in rhesus and cynomolgus monkeys was studied in vivo and in vitro. In stop-flow experiments in ketamine-anesthetized monkeys, the ratios of urine/plasma MTX concentration to urine/plasma inulin concentration of proximal tubular samples were about 2-fold greater than the base-line free-flow values of 3.3 to 4.8, indicating net proximal tubular secretion. MTX secretion was inhibited by penicillin, which lowered the base-line U/PMTX/U/Pinulin ratios to 0.8 to 1.3; the effect persisted over a 30-min period after discontinuation of penicillin administration. Penicillin also slowed the disappearance of MTX from plasma over a 2-hr period after i.v. bolus administration of MTX. In experiments with renal cortical slices, MTX uptake at 25 degrees was linear over the initial 30 min. The uptake Km and Vmax were 0.09 mM and 0.11 mumol/g of tissue/30 min, respectively. Penicillin competitively inhibited MTX uptake; the Ki was 0.83 mM. MTX efflux from preloaded slices (incubated with 0.5 mM MTX for 45 min) was a first-order process with an initial t1/2 of 7.1 min, which decreased to 2.0 min in the presence of 1.36 mM penicillin. It was concluded that MTX and penicillin share a common secretory system in the kidney and that penicillin blocks MTX secretion by inhibiting cellular uptake and stimulating efflux.