Disposition of Cefotaxime and Its Metabolite, Desacetylcefotaxime, in Rat: Application of a Pharmacokinetic-Protein Binding Model

Abstract

1. The pharmacokinetics and protein binding of cefotaxime and desacetylcefotaxime were studied in rat.

2. After i.v. dosing of cefotaxime (100mg/kg) the concentration-time profiles of cefotaxime and its metabolite desacetylcefotaxime followed biphasic decays, giving the kinetic parameters for cefotaxime: V^T_ss and AUC of 127ml/kg and 8.2mg/min per ml, respectively. The β-elimination half-life was 17 min with Cls of 13.1 ml/min per kg. The average association constant (K x 10³M⁻¹) and total protein binding site concentration (Pt x 10⁻³M) for cefotaxime were 3.87 and 0.68, respectively, with saturation of plasma protein binding occurring at about 30 μg/ml. The average free fraction of cefotaxime in plasma (F_p) was 0.48.

3. The metabolite desacetylcefotaxime had a plasma C_max of 74.4μg/ml (35 min). The respective elimination half-life and AUC were 53 min and 7.2 mg/min per ml. The binding profile, unlike that of cefotaxime, was non-saturable with a K value of 13.90M_-1. The F_p of desacetylcefotaxime was 0.89.

4. The concentration-time behaviour of total and free desacetylcefotaxime (i.v. bolus, 50mg/kg) declined biexponentially with respective V^Tss and AUC of 125ml/kg and 19.4 mg/min per ml (total drug), and 192 ml/kg and 13.9 mg/min per ml (free drug). The β-phase half-life of total and free drug was about 36 min, whereas CLs (ml/min per kg) were 2.7 (total) and 3.7 (free). The binding characteristics were in good agreement with those of the metabolite produced in vivo, with a K value of 8.58M⁻¹. The F_p value of desacetylcefotaxime in plasma was 0.73.