THE DISPOSITION AND RENAL HANDLING OF ENPROFYLLINE IN ENDOTOXEMIC RATS BY BACTERIAL LIPOPOLYSACCHARIDE (LPS)

The effects of lipopolysaccharide (LPS), isolated from Klebsiella pneu moniae (03:Kl-), on the pharmacokinetic behavior and renal handling of enprofylline, which is mainly excreted into the urine by an active tu bular secretion mechanism, were investigated in rats. LPS (50 and 250 mug/kg) was infused for 20 to 30 min 2 hr before an intravenous admini stration of enprofylline (2.5 mg/kg). LPS induced a decresse in the sy stemic clearance and an increase in the volume of distribution at the steady state of enprofylline without any histological changes in the k idneys. No changes in the protein-binding parameters of enprofylline w ere observed between the control and LPS-pretreated groups, although L PS slightly decreased the albumin concentration in plasma. LPS caused decreases in the apparent maximum capacity of transport (V(max)) from 71.24 to 15.02 mug/min, in the Michaelis-Menten constant (K(M)) from 3 .04 to 1.42 mug/ml, and in the glomerular filtration rate as estimated for inulin clearance from 3.10 to 1.87 ml/min. These results indicate that LPS decreases both the affinity and capacity of the tubular tran sport system, and in turn decreases the tubular secretory intrinsic cl earance of enprofylline as shown by V(max)/K(M). The mechanism for ind ucing changes in the pharmacokinetic behavior and renal handling of en profylline by LPS may be related to the effects of LPS on tubular secr etion of enprofylline and its distribution in the organs and periphera l tissues.