INFLUENCE OF PIPERACILLIN ON THE PHARMACOKINETICS OF METHOTREXATE AND7-HYDROXYMETHOTREXATE

The influence of concomitant administration of piperacillin (PIP) on t he pharmacokinetic parameters of methotrexate (MTX) and 7-hydroxymetho trexate (7-OH-MTX) was studied in rabbits. Six rabbits received an ini tial i.v. bolus (0.21 mg kg(-1)) followed by a constant-rate i.v infus ion of the drug (5 mu g 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 per iod. The control group consisted of four rabbits treated the same way except for the addition of PIP. There were significant increases in th e mean residence times found for MTX (MRTinf) and 7-OH-MTX (MRTm,inf) following PIP administration. Concomitant administration of PIP with M TX also produced significant 1.5- and 2.8-fold increases in the area u nder the curve of MTX and 7-OH-MTX, respectively. The total body clear ance of MTX and the operative total body clearance of 7-OH-MTX signifi cantly decreased, but in a less than proportional manner. The study de monstrates that the interaction between MTX and PIP is mainly due to t he reduced clearance of both MTX and 7-OH-MTX combined with a slight i ncrease in the formation clearance of the metabolite.