Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics

Abstract

The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose‐dependent increase in total systemic clearance (Cl^T_S) from 9.7 ml/min at the 150‐mg dose to 13 ml/min at the 1500‐mg dose. The dose‐dependent changes in Cl^T_S could be explained in terms of the concentration‐dependent plasma protein binding of ceftriaxone (f_plasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUC^F_0–∞) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (CI^F_R) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (CI^F_R) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t½ was not influenced by dose and averaged 8 hr. This biologic t½ is by far the longest ever for a cephalosporin in healthy subjects. Clinical Pharmacology and Therapeutics (1981) 29, 650–657; doi:10.1038/clpt.1981.90