Pharmacokinetics of mezlocillin in healthy volunteers

Mezlocillin in doses of 1.0, 2.0, and 5.0 g and carbenicillin in doses of 2.0 g were given as bolus injections intravenously to 10 healthy volunteers. For mezlocillin, dose-dependent pharmacokinetics was detected. This is reflected by a more than proportional rise in serum concentrations and a decreased total body clearance as doses were increased. Per dose unit, the areas under serum concentration curves to infinity were 33.5 mug.h/ml for the 1.0-g dose, 47.2 mug.h/ml for the 2.0-g dose, and 54.8 mug.h/ml for the 5.0-g dose. The body clearance fell from 31.2 liters/h with the 1.0-g dose to 17.0 liters/h with the 5.0-g dose. This can be explained mainly by a marked depression of nonrenal clearance, which fell from 12.2 to 3.8 liters/h, compared with a parallel change in renal clearance from 19.0 to 13.2 liters/h. Contributing to the non-linearity may be biotransformation, evacuation via bile, or another process. With dose increments, rising amounts are recovered unchanged in the urine-61% after a 1.0-g dose compared with 69% after a 5.0-g dose. This clearly defines metabolism as a major factor of elimination. Carbenicillin, for which the first-order, two-compartment open model was applicable here as in previous studies, had a longer serum half-life than did mezlocillin. For the 2.0-g doses, the former had a half-life of 1.4 h, compared with 0.8 h for the latter (calculated as if the two-compartment model were fully valid). The relative area under the curve (see above) was 76.1 mug.h/ml after the 2.0-g dose.