TIME-DEPENDENT CHANGES IN THE PHARMACOKINETICS AND RENAL EXCRETION OFXANTHINE DERIVATIVE ENPROFYLLINE INDUCED BY BACTERIAL-ENDOTOXIN IN RATS

Time-dependent changes in the pharmacokinetics and renal handling of e nprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kid ney functions and the renal excretion of enprofylline, which is an org anic anion drug excreted primarily by an active tubular secretion, LPS (250 mu g/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 mu g/min/kg for inulin and enprofylline, respectively. L PS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the cont rol rats within 30 min after the LPS treatment. The renal clearance (C L(r)) of enprofylline decreased in conjunction with GFR, while the per centage of decrease in the CL(r) was slightly greater than that in GFR . LPS-induced decreases in the CL(r) for enprofylline and GFR continue d over the testing period of 120 min. The time-dependent effect of LPS on the pharmacokinetics of enprofylline was examined by a single inje ction of enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24h earl ier with or without LPS. The pharmacokinetic parameters of enprofyllin e were determined by a model-independent method. Significant changes i n the systemic clearance for enprofylline were observed in rats pretre ated 2 and 10 h earlier with LPS, but no such changes were observed in rats pretreated 24h earlier with LPS. These findings indicate the exi stence of a time-dependent effect of LPS on the pharmacokinetics of en profylline, and suggest that LPS at a dose of 250 mu g/kg, at least, d oes not induce cytotoxicity to kidney cells.