Disposition, metabolism, and excretion of [14C]doripenem after a single 500-milligram intravenous infusion in healthy men.
In this open-label, single-center study, eight healthy men each received a single 500-mg dose of [(14)C]doripenem, containing 50 microCi of [(14)C]doripenem, administered as a 1-h intravenous infusion. The concentrations of unchanged doripenem and its primary metabolite (doripenem-M-1) resulting from beta-lactam ring opening were measured in plasma and urine by a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Total radioactivity was measured in blood, plasma, urine, and feces by liquid scintillation counting. Further metabolite profiling was conducted on urine samples using liquid chromatography coupled to radiochemical detection and high-resolution mass spectrometry. Unchanged doripenem and doripenem-M-1 accounted for means of 80.7% and 12.7% of the area under the plasma total-radioactivity-versus-time curve (area under the concentration-time curve extrapolated to infinity) and exhibited elimination half-lives of 1.1 and 2.5 h, respectively. Total clearance of doripenem was 16 liters/h, and renal clearance was 12.5 liters/h. At 7 days after the single dose, 95.3% of total doripenem-related radioactivity was recovered in urine and 0.72% in feces. A total mean of 97.2% of the administered dose was excreted in the urine as unchanged doripenem (78.7% +/- 5.7%) and doripenem-M-1 (18.5% +/- 2.6%). Most of the urinary recovery occurred within 4 h of dosing. Three additional minor metabolites were identified in urine: the glycine and taurine conjugates of doripenem-M-1 and oxidized doripenem-M-1. These results show that doripenem is predominantly eliminated in urine as unchanged drug, with only a fraction metabolized to doripenem-M-1 and other minor metabolites.
Cirillo
Iolanda
I
Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 920 Route 202 South, Raritan, NJ 08869, USA. icirillo@prdus.jnj.com
Mannens
Geert
G
Janssen
Cor
C
Vermeir
Marc
M
Cuyckens
Filip
F
Desai-Krieger
Daksha
D
Vaccaro
Nicole
N
Kao
L Mark
LM
Devineni
Damayanthi
D
Redman
Rebecca
R
Turner
Kenneth
K
D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D015780:Carbapenems / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid; D015331:Cohort Studies; D000077726:Doripenem; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012449:Safety; D053719:Tandem Mass Spectrometry
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002250:Carbon Radioisotopes; D000077726:Doripenem