Pharmacokinetics and Protein Binding of Cefamandole and Its 1-methyl-1 H-tetrazole-5-thiol Side Chain in Subjects with Normal and Impaired Renal Function

The 1-methyl-1 H-tetrazole-5-thiol (MTT) side chain present on several new cephalosporins may be an important factor in coagulopathy observed during therapy with these antibiotics. To determine the plasma kinetics and protein binding of the side chain and to test the hypothesis that renal failure alters these parameters, we gave six normal volunteers and six anuric patients a single iv dose of 15 mg of cefamandole/kg. Plasma concentrations of cefamandole and free MTT were measured by high-performance liquid chromatography 14 times during the 48-hr period after the dose was given. A compartment-independent pharmacokinetic analysis showed that MTT was rapidly removed from the plasma of normal subjects, but that peak concentrations of MTT were nearly three times greater and persisted for 48 hr in patients with renal failure. Further, renal failure caused a significant MTT protein-binding defect. If a relation exists between hypoprothrombinemia and plasma concentrations of MTT side chain, patients with reduced renal function may be at increased risk for this adverse effect.