Influence of piperacillin on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate

The influence of concomitant administration of piperacillin (PIP) on the pharmacokinetic parameters of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) was studied in rabbits. Six rabbits received an initial i.v. bolus (0.21 mg kg⁻¹) followed by a constant-rate i.v. infusion of the drug (5 μg min⁻¹ kg⁻¹) for 240 min. The PIP dose (30 mg kg⁻¹) was repeated every 30 min until the end of the infusion period. The control group consisted of four rabbits treated the same way except for the addition of PIP. There were significant increases in the mean residence times found for MTX (MRT_inf) and 7-OH-MTX (MRT_m,inf) following PIP administration. Concomitant administration of PIP with MTX also produced significant 1.5- and 2.8-fold increases in the area under the curve of MTX and 7-OH-MTX, respectively. The total body clearance of MTX and the operative total body clearance of 7-OH-MTX significantly decreased, but in a less than proportional manner. The study demonstrates that the interaction between MTX and PIP is mainly due to the reduced clearance of both MTX and 7-OH-MTX combined with a slight increase in the formation clearance of the metabolite. Received: 9 March 1998 / Accepted: 14 May 1998