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.
Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. bradley_wong@merck.com
B K
BK
Wong
Y
Y
Sahly
G
G
Mistry
S
S
Waldman
D
D
Musson
A
A
Majumdar
X
X
Xu
S
S
Yu
J H
JH
Lin
R
R
Singh
S
S
Holland
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