Effect of Penicillin on the Renal Tubular Secretion of Methotrexate in the Monkey¹ Free

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/P_MTX/U/P_inulin 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° was linear over the initial 30 min. The uptake K_m and V_max were 0.09 mm and 0.11 µmol/g of tissue/30 min, respectively. Penicillin competitively inhibited MTX uptake; the K_i 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 t_½ 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.