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.