Time-Dependent Changes in the Pharmacokinetics and Renal Excretion of Xanthine Derivative Enprofylline Induced by Bacterial Endotoxin in Rats

Time-dependent changes in the pharmacokinetics and renal handling of enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250μg/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 μg/min/kg for inulin and enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CL_r) of enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CL_r was slightly greater than that in GFR. LPS-induced decreases in the CL_r for enprofylline and GFR continued over the testing period of 120min. The time-dependent effect of LPS on the pharmacokinetics of enprofylline was examined by a single injection of enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24h earlier with or without LPS. The pharmacokinetic parameters of enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for enprofylline were observed in rats pretreated 2 and 10h earlier with LPS. but no such changes were observed in rats pretreated 24h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of enprofylline, and suggest that LPS at a dose of 250 μg/kg, at least, does not induce cytotoxicity to kidney cells.