Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats.
The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing.
Novartis Biomedical Research Institute, East Hanover, New Jersey, USA.
Wen
W
Lin
Novartis Biomedical Research Institute, East Hanover, New Jersey, USA.
Jimmy
J
Flarakos
Novartis Biomedical Research Institute, East Hanover, New Jersey, USA.
Yancy
Y
Du
Novartis Biomedical Research Institute, East Hanover, New Jersey, USA.
Wenyu
W
Hu
Novartis Biomedical Research Institute, East Hanover, New Jersey, USA.
Handan
H
He
Novartis Biomedical Research Institute, East Hanover, New Jersey, USA.
James
J
Mangold
Paratek Pharmaceuticals, Boston, Massachusetts, USA.
S Ken
SK
Tanaka
Paratek Pharmaceuticals, Boston, Massachusetts, USA stephen.villano@paratekpharma.com.
Stephen
S
Villano
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D004334:Drug Administration Schedule; D006207:Half-Life; D006243:Harderian Gland / Q000187:drug effects / Q000378:metabolism*; D065669:Hepatobiliary Elimination / Q000502:physiology; D066237:Intestinal Elimination / Q000502:physiology; D008297:Male; D008543:Melanins / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D013754:Tetracyclines / Q000097:blood / Q000493:pharmacokinetics*; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D008543:Melanins; D013754:Tetracyclines; C000591640:omadacycline
ADME; aminomethylcycline; animal models; omadacycline