RENAL EXCRETION OF FAMOTIDINE AND ROLE OF ADENOSINE IN RENAL-FAILURE INDUCED BY BACTERIAL LIPOPOLYSACCHARIDE IN RATS

Our previous studies have reported that bacterial lipopolysaccharide ( LPS) dramatically changes the ability of the active tubular anion secr etory system in rats. The present study has investigated the effects o f LPS on the pharmacokinetics and renal handling of famotidine, an org anic cation drug excreted primarily by an active tubular secretion mec hanism in rats. The role of adenosine in the LPS-induced renal failure was also investigated using theophylline, an adenosine antagonist. Pr etreatment with LPS (250 mu g/kg) significantly decreased the steady-s tate volume of distribution, systemic clearance, and renal clearance ( CL(r)) of famotidine, but not nonrenal clearance. No significant diffe rences in total urinary recovery of unchanged famotidine were observed between treatments. Pretreatment with LPS significantly decreased the glomerular filtration rate (GFR), estimated as inulin clearance. LPS increased the clearance ratio of famotidine (CL(r)/GFR), but not the n et tubular secretion, indicating that LPS has little or no effect on t he active tubular cation secretory system. Theophylline (10 mg/kg) imp roved LPS induced decrease in GFR without causing any changes in the p harmacokinetic parameters of famotidine. These findings provide furthe r evidence that LPS produces different effects on the distribution and the active tubular secretory systems of anion and cation drugs, and t hat adenosine may play an important role in the induction of renal fai lure by LPS.