Nonlinear mezlocillin kinetics due to dose-dependent metabolism

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Abstract
Dose-dependent kinetics of i.v. bolus-dose mezlocillin, a newly developed ureidopenicillin [antibiotic] were studied. Renal, biliary and total clearance were examined at different steady-state levels in 8 healthy subjects. After infusion of doses of 22.4 .+-. 1.5, 11.4 .+-. 0.7 and 5.6 .+-. 0.4 mg/min mean plasma steady-state levels of 88.4 .+-. 15.9, 40.3 .+-. 7.5 and 18.4 .+-. 4.6 .mu.g/ml were achieved. Metabolic clearance was estimated as the difference between total clearance and the sum of renal and biliary clearance, assuming that no other route of excretion plays an important role in the elimination of the drug. Total clearance varied between 355.7 .+-. 59.3 and 286.5 .+-. 54.6 ml/min when doses of 5.6 .+-. 0.4 and 22.4 .+-. 1.5 mg/min were given. Since neither renal clearance (137.6 .+-. 32.6 ml/min) nor biliary clearance (98.6 .+-. 42.5 ml/min) was shown to be dose dependent, nonlinear mezlocillin kinetics must be due to dose dependent metabolic clearance (108.4 .+-. 26.2 vs. 60.2 .+-. 32.3 ml/min at 5.6 .+-. 0.4 and 22.4 .+-. 1.5 mg/min). The apparent Km was 27.5 .mu.g/ml and apparent Vmax [maximum metabolic rate] 4.3 mg/min. The apparent Km is so low that after therapeutic doses of mezlocillin the kinetics are nonlinear for several hours.

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