ALTERATIONS IN PHARMACOKINETICS AND PROTEIN-BINDING BEHAVIOR OF CEFAZOLIN IN ENDOTOXEMIC RATS

The possible alterations in the pharmacokinetics and protein binding b ehavior of the beta-lactam antibiotic cefazolin (CEZ) were investigate d in endotoxemic rats induced by Klebsiella pneumoniae O3 lipopolysacc haride (LPS). LPS (250 mug/kg of body weight) was infused for 20 to 30 min 2 h before an intravenous administration of CEZ (20 mg/kg). Signi ficant decreases in systemic clearance and renal clearance of CEZ were observed in LPS-treated rats without any changes in fraction of urina ry excretion in unchanged CEZ (>0.8). The volume of distribution at st eady state showed a tendency to increase. The protein binding paramete rs of CEZ, the binding capacity, and number of binding sites on the al bumin molecule were decreased by LPS, whereas the dissociation constan t did not change. Significant decreases in systemic and renal clearanc es for unbound CEZ were observed in LPS-treated rats. The glomerular f iltration rate estimated as inulin clearance was also decreased by LPS . The ratio of renal clearance of unbound CEZ to glomerular filtration rate (clearance ratio) dropped to 70% of that in control rats, and th e net tubular secretion of CEZ was also dramatically reduced. The pres ent study suggests that LPS has an effect on the pharmacokinetics of C EZ by changes which occur in renal handling and protein binding.