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Steady-state plasma and tissue concentrations of tigecycline after intravenous infusion administration to rabbits

Abstract number: R2093

Zorpas K., Charkoftaki G., Vryonis E., Dokoumetzidis A., Kostomitsopoulos N., Skoutelis A., Archontaki H., Valsami G.

Background: Tigecyclin (T) is the first available glycycycline derived from minocycline. It possesses broad-spectrum activity against aerobic and anaerobic bacteria including multidrug resistant Gram positive and Gram negative pathogens.

Trigecyclin was found to exhibit large volume of distribution in healthy humans, indicating extensive tissue distribution and half-life elimination of 37 to 67 hours. With a single intravenous (IV) dose of 7 or 14 mg/kg in rabbits the drug concentration in serum can remain above the MIC for more than 12 hours.

Objectives: To measure T accumulation to body tissues at steady state in order to construct a full body physiological based PK model and to describe drug disposition kinetics in rabbits.

Methods: We used New Zealand white rabbits (3.0±0.4 kg). After a loading IV dose of 75 mg T in 15 min, animals received 27.5 mg of T during a 2.5 h continuous IV infusion to achieve a 2 mg/mL plasma steady state concentration (SSC). Blood sample measurement at 60, 45, 30 and 15 min prior and immediately after the end of the 2.5 h IV infusion were used to confirm SSC. At the end of the 2.5 h IV infusion all rabbits were anaesthetized and sacrificed. Tissue samples were taken to determine drug accumulation. Blood samples were centrifuged at 4000 rpm for 15 min and plasma samples were frozen at -70°C until analyzed. Tigecycline assay was performed by a HPLC-UV method recently developed in our laboratory and properly modified for the needs of this study.

Results: The result are presented in the table.

Conclusion: Results show that in rabbits T accumulates to well perfused tissues such as kidneys, liver, spleen, muscle and testicular tissue. Due to its hydrophilic nature tigecycline concentration in fat tissues is low and is not distributed in the brain.

OrganConcentration (mg/g)OrganConcentration (mg/g)
Heart7.83 (±3.4)Peritoneal fat1.6 (±0.5)
Spleen11.3 (±2.2)Orbital fat4.8 (±2.2)
Liver38.5 (±16.4)Bone marrow0.3 (±0.1)
Kidneys20.9 (±9.0)Brain0.3 (±0.03)
Gallbladder70.1 (±21.5)Lung7.8 (±2.0)
Bile200.0 (±80.5)Testicular tissue6.8 (±1.4)
Thigh muscle10.4 (±4.4)Vitreous fluid0.4 (±0.1)

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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