Cephalosporins increase the renal clearance of methotrexate and 7-hydroxymethotrexate in rabbits.
Anaesthetized rabbits were infused with methotrexate (MTX; 30 micrograms x kg-1 x min-1) for 4 h. Constant plasma concentrations of MTX and its main metabolite 7-hydroxymethotrexate (7-OH-MTX) were achieved 40-60 min after the start of the infusion. In all, 50% of the infused MTX was eliminated by the kidney; another 15%-30% was hydroxylated and excreted as 7-OH-MTX in the urine. A concomitant infusion of penicillin G (3.96 mg x kg-1 x min-1) decreased the renal clearance of MTX and 7-OH-MTX, probably by competitive antagonism at the common tubular secretion site. In contrast, the four cephalosporins ceftriaxone, ceftazidime, ceftizoxime and cefoperazone all increased the renal clearance of MTX and 7-OH-MTX. At similar plasma concentrations, ceftriaxone and ceftazidime were almost equipotent, ceftizoxime was less effective and cefoperazone seemed to have a biphasic effect, depressing the clearance of MTX and 7-OH-MTX at higher drug concentrations. The effects are best explained by an inhibition of the tubular reabsorption of the cytostatic and its metabolite. The results suggest that cephalosporins are a better choice than penicillin for antibiotic treatment during MTX therapy.
Department of Pharmacology, Medical University of Lübeck, Federal Republic of Germany.
H
H
Iven
H
H
Brasch
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D002442:Ceftazidime / Q000493:pharmacokinetics; D002511:Cephalosporins / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D010400:Penicillin G / Q000493:pharmacokinetics; D011817:Rabbits; D013997:Time Factors
D000970:Antineoplastic Agents; D002511:Cephalosporins; D005493:Folic Acid Antagonists; D002442:Ceftazidime; D010400:Penicillin G; C011864:7-hydroxymethotrexate; D008727:Methotrexate