The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits.

In anesthetized rabbits, continuous infusion of methotrexate (MTX; 30 micrograms kg-1 min-1) established steady-state plasma concentrations for MTX and the metabolite 7-hydroxymethotrexate (7-OH-MTX) within 40 min. Fifty percent of the infused dose was eliminated unchanged by the kidneys and the renal MTX clearance was slightly higher than the inulin clearance. Another 15%-30% was metabolized and excreted as 7-OH-MTX in the urine. Infusions of 7-OH-MTX, furosemide or benzarone had no influence on the clearance of MTX or 7-OH-MTX. Infusions of probenecid or piperacillin decreased the renal clearance of MTX and 7-OH-MTX mainly by reducing the tubular secretion of both compounds. In contrast, infusions of the antibiotics ceftriaxone and sulfamethoxazole increased the renal elimination of MTX and 7-OH-MTX. An increase was also observed during the infusion of the uricosuric drugs sulfinpyrazone and benzbromarone. These results are consistent with competition for tubular reabsorption between MTX, ceftriaxone and sulfamethoxazole. The pharmacokinetic drug interactions observed occurred with therapeutic drug concentrations and thus may be clinically relevant.