Influence of the antibiotics piperacillin, doxycycline, and tobramycin on the pharmacokinetics of methotrexate in rabbits.
In rabbits methotrexate (MTX) plasma concentrations showed a triexponential decline after short-term infusion (12 mg/kg in 10 min). Probenecid (50 mg/kg PO 1 h before MTX) and piperacillin (100 mg/kg SC 10 min before MTX plus 50 mg/kg SC 4 h later) increased the plasma concentrations of MTX and its metabolite 7-hydroxy-methotrexate (7-OH-MTX) 40 min to 6 h after the end of MTX infusion. The total body clearance of MTX was reduced, while the elimination half-life and the drug distribution to the peripheral body compartments were unchanged. Doxycycline (5 mg/kg PO 30 min before MTX) had no influence on the pharmacokinetics of MTX. Tobramycin was ineffective when given either only on the day of MTX infusion (2 mg/kg SC, 5 min before MTX and 2 mg/kg SC 4 h later) or as a 5-day pretreatment (2 X 2 mg/kg SC daily). The influence of probenecid and piperacillin can be explained by a reduction of the renal elimination of MTX via the tubular transport mechanism for organic acids. This interaction occurred with therapeutic drug concentrations and thus may be clinically relevant.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology; D004347:Drug Interactions; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000097:blood*; D010878:Piperacillin / Q000494:pharmacology; D011339:Probenecid / Q000494:pharmacology; D011817:Rabbits; D014031:Tobramycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004318:Doxycycline; D011339:Probenecid; D014031:Tobramycin; D010878:Piperacillin; D008727:Methotrexate