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Cephalosporins increase the renal clearance of methotrexate and 7-hydroxymethotrexate in rabbits
1Department of Pharmacology, Medical University of Lübeck, Federal Republic of Germany.
Abstract:
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.
Insights
Certain cephalosporins enhance methotrexate (MTX) and its metabolite renal clearance, suggesting they are preferable to penicillin G for co-administration during MTX therapy.
Area of Science:
- Pharmacology
- Nephrology
- Oncology
Background:
- Methotrexate (MTX) is a crucial chemotherapeutic agent.
- Understanding drug interactions affecting MTX renal clearance is vital for optimizing therapy and minimizing toxicity.
- Penicillin G and cephalosporins are commonly used antibiotics that may interact with MTX.
Purpose of the Study:
- To investigate the effects of penicillin G and four cephalosporins (ceftriaxone, ceftazidime, ceftizoxime, cefoperazone) on the renal clearance of methotrexate (MTX) and its metabolite 7-hydroxymethotrexate (7-OH-MTX) in rabbits.
Main Methods:
- Anesthetized rabbits were infused with MTX.
- Concomitant infusions of penicillin G or various cephalosporins were administered.
- Plasma concentrations and renal clearance of MTX and 7-OH-MTX were measured.
Main Results:
- Penicillin G decreased the renal clearance of MTX and 7-OH-MTX.
- Ceftriaxone, ceftazidime, ceftizoxime, and cefoperazone increased the renal clearance of MTX and 7-OH-MTX.
- Cephalosporin effects were attributed to inhibition of tubular reabsorption, with varying potency.
Conclusions:
- Cephalosporins appear to be a better choice than penicillin G for antibiotic treatment during MTX therapy due to their favorable impact on MTX renal clearance.