Comparative disposition of [14C]ertapenem, a novel carbapenem antibiotic, in rat, monkey and man.
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.
Wong
B K
BK
Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. bradley_wong@merck.com
Sahly
Y
Y
Mistry
G
G
Waldman
S
S
Musson
D
D
Majumdar
A
A
Xu
X
X
Yu
S
S
Lin
J H
JH
Singh
R
R
Holland
S
S
D000328:Adult; D000818:Animals; D015780:Carbapenems / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D000077727:Ertapenem; D005243:Feces / Q000737:chemistry*; D005260:Female; D006801:Humans; D007769:Lactams / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009928:Organ Specificity; D011865:Radioisotope Dilution Technique; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution; D047090:beta-Lactams
D015780:Carbapenems; D002250:Carbon Radioisotopes; D007769:Lactams; D019275:Radiopharmaceuticals; D047090:beta-Lactams; D000077727:Ertapenem