Pharmacokinetics of a new cephalosporin, cefotaxime (HR 756) in patients with different renal functions.

Abstract

The pharmacokinetics of intramuscular doses of 1.0 g cefotaxime (HR 759) was studied in 19 persons with normal or reduced renal function. Quantitation was done by both microbiological and high pressure liquid chromatography (HPLC) methods. The HPLC determined unchanged cefotaxime and desacetyl cefotaxime and up to 2 more metabolites in serum, whether unchanged or biotransformed. Patients with renal functions within the normal range (inulin clearance above 100 ml/min) had a mean serum peak concentration of 24.5 ± 10.5 μg/ml. In renal failure, both serum concentrations and the terminal serum half-life (t½β) increased. The mean terminal serum half-life was 2.1 h according to the microbiological assay and 1.5 h according to the HPLC procedure at a glomerular filtration rate (GFR) of 100 ml/min. At an inulin clearance of 10 ml/min, the serum half-life was 6.0 h for the total microbiologically assayed activity and 3.6 h for unchanged drug. There is a linear relationship between log serum half-life of the three moieties of unchanged cefotaxime, total antimicrobial activity (agar diffusion assay with Escherichia coli as indicator), and the major metabolite desacetyl cefotaxime and log clearance of both inulin (ClI) and p-amino-hippuric acid (CIPAH) down to CII, of 10 ml/min. The excretion of unchanged drug in urine during 24 h was reduced gradually upon reduction in renal function from a mean of 59.4 ± 10.2% (range 52.1–77.1) in 5 subjects with GFR above 100 ml/min. The area volume of distribution, e.g. the area of the one-compartment linear open model or during the β-phase of the two-compartment model, Vd,area, was 34.3 ± 10.4 litres according to the microbiological assay and 27.3 ± 13.4 litres for unchanged cefotaxime in patients with renal function within the normal range. The patients with reduced renal function had only insignificantly different distribution volumes. The volumes in normal individuals correspond to 53% of the body weight. The deasacetyl cefotaxime metabolite is excreted more slowly than the parent compound and elimination is relatively longer compared to the parent compound in patients with reduced renal functions. Doses for patients with reduced renal function are discussed. Because nonrenal mechanisms of elimination assume importance when the renal route becomes inefficient, elimination is only moderately prolonged, even in patients with severe renal impairment. Therefore, only moderate reduction in dosage seems necessary.