The total (bound and unbound) plasma concentration time profiles following the three intravenous doses of Rocephin (150, 500 and 1,500 mg) declined in a biphasic manner. A simple compartment analysis was inappropriate since a dose-disproportional increase in the area under the total drug concentration time curve (AUCT,0(-8)) occurred. This resulted in unstable, dose-dependent total systemic clearance (9.7-13.0 ml/min) and volume of distribution (7.0-8.6 litres) values. The dose-dependent pharmacokinetic changes could be completely explained in terms of the concentration-dependent plasma protein binding (fp ranging from 0.04 to 0.17 in the concentration range from 0.5 to 300 micrograms/ml). Hence, the pharmacokinetics of free (unbound) Rocephin was linear and dose-independent. With reference to free (unbound) drug the mean total clearance was 255 ml/min and the mean renal clearance about 160 ml/min. The renal clearance was therewith slightly higher than the average glomerular filtration rate in man (approximately 125 ml/min). Consequently the coadministration of probenecid (1 g) had no effect on the pharmacokinetics of Rocephin. The mean plasma half-life of Rocephin was not influenced by dose and averaged 8 h. It was therewith the longest ever reported one for a cephalosporin in healthy volunteers.