Comparative disposition of [¹⁴C]ertapenem, a novel carbapenem antibiotic, in rat, monkey and man

Abstract

1. The disposition and metabolism of ertapenem, a carbapenem antibiotic, was examined in rat, monkey and man. Sprague–Dawley rats and Rhesus monkeys were given, by intravenous administration, radiolabelled doses of ertapenem (60 and 30 mg kg⁻¹, respectively), and healthy normal volunteers received a single fixed dose of 1000 mg. Urine and faeces were collected for determination of total radioactivity.

2. In healthy volunteers, [¹⁴C]ertapenem was eliminated by a combination of hydrolytic metabolism to a beta-lactam ring-opened derivative and renal excretion of unchanged drug. Approximately equal amounts were excreted as a beta-lactam ring-opened metabolite and unchanged drug (36.7 and 37.5% of dose, respectively). A secondary amide hydrolysis product accounted for about 1% of the dose in man. About 10% of the administered radioactivity was recovered in faeces, which suggested that a minor fraction underwent biliary and/or intestinal excretion.

3. In animals, a greater fraction of the dose was eliminated via metabolism; excretion of unchanged drug accounted for 17 and 5% of dose in rats and monkeys, respectively. In monkeys, the beta-lactam ring-opened and amide hydrolysis metabolites accounted for 74.8 and 7.59% of the dose, respectively, whereas in rats, these metabolites accounted for 31.9 and 20% of dose, respectively.

4. In vitro studies with fresh rat tissue homogenates indicated that lung and kidney were the primary organs involved in mediating formation of the beta-lactam ring-opened metabolite. The specific inhibitor of dehydropeptidase-I, cilastatin, inhibited the in vivo and in vitro metabolism of ertapenem in rats, which suggested strongly that the hydrolysis of ertapenem in lung and kidney was mediated by this enzyme.