Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics.
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 (ClTS) from 9.7 ml/min at the 150-mg dose to 13 ml/min at the 1500-mg dose. The dose-dependent changes in ClTS could be explained in terms of the concentration-dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCFO-infinity) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (ClFS) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (ClFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t1/2 was not influenced by dose and averaged 8 hr. This biological t1/2 is by far the longest ever for a cephalosporin in healthy subjects.
D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D002443:Ceftriaxone; D002511:Cephalosporins / Q000097:blood* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D011485:Protein Binding
D001798:Blood Proteins; D002511:Cephalosporins; D002443:Ceftriaxone