Date of Graduation
1996
Document Type
Thesis
Abstract
Ceftriaxone (CRO) is a third generation cephalosporin with a long half-life. The majority of patients with severe renal failure have slightly increased half-lives but a small subset of patients exhibit strikingly prolonged half-lives. The reduced ability of this minority of patients to eliminate CRO by biliary excretion will result in excessive drug accumulation. Therefore, the series of studies included in this dissertation were proposed to develop a renal failure model in rats, to examined the pharmacokinetics of CRO in this animal model, and to explore the biliary excretion mechanisms of CRO. Rats pretreated with uranyl nitrate exhibited a dramatic increase of serum urea nitrogen level and a renal clearance of total CRO approaching zero with a slightly prolonged half-life. The biliary clearance of CRO did not change in these rats and the protein binding of CRO was significantly reduced in uremic serum. The rat model of renal failure appears to be satisfactory for the study of the factors controlling the clearance/half-life of CRO in renal failure. The biliary excretion rate of bile acids is significantly correlated with that of CRO in healthy humans. Therefore, the effect of a model bile acid (tauroursodeoxycholate, TUDC) on the biliary clearance of CRO was studied. It was observed that the biliary clearance of total CRO decreased approximately 50% during TUDC infusion and recovered promptly after the discontinuation of TUDC treatment. These findings support the view that TUDC reversibly inhibited the biliary excretion of CRO in rats with or without renal failure. Apparently, CRO is at least partly excreted into bile via a transport system shared with TUDC. A small number of rats with normal kidney function exhibited very low biliary excretion of CRO. This might be attributable to an inherently defective biliary transport system or accumulation of substances which compete with this drug for this transport system. Overall, the findings of these studies significantly improve the understanding of the biliary clearance of CRO.
Recommended Citation
Zhao, Qinying, "Studies of renal and biliary clearance in severe kidney dysfunction: Development of a rat model mimicking the pharmacokinetics of ceftriaxone in man." (1996). Graduate Theses, Dissertations, and Problem Reports. 10108.
https://researchrepository.wvu.edu/etd/10108