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Tissue Penetration of a Novel Spectinamide Antibiotic for the Treatment of Tuberculosis

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Abstract

The in vivo biodistribution and pharmacokinetics of 1329, a novel spectinamide antibiotic with anti-tubercular activity, were studied during intravenous administration of an tritium-labeled compound for nine consecutive, 12-hourly doses to rats. Serial blood samples were collected after the first and the eighth dose, and major organs and tissues were collected 1 h after the ninth dose. Urinary and fecal excretion was monitored throughout the dosing period. Radioactivity in the collected samples was assessed by scintillation counting. During the course of treatment, 86.6% of the administered radioactivity was recovered in urine, feces, organs, and muscle tissue. Urinary excretion was the major route of elimination, with 70% of radioactivity recovered from urine and 12.6% from feces. The time profiles of radioactivity in serum after the first and the eighth dose were identical for the first 2 h post-dose, with similar Cmax (3.39 vs. 3.55 mCi/L) and AUC0−τ (5.08 vs. 5.17 mCi • h/L), indicating no substantial accumulation of 1329 during multiple dosing. Radioactivity in major target organs for pulmonary tuberculosis infection, the lungs and spleen, was 2.79- and 3.06-fold higher than in the blood. Similarly, the intracellular uptake of 1329 into macrophages was sixfold higher than for streptomycin. Overall, these observations suggest biodistribution properties favorable for targeting pulmonary tuberculosis infections.

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Acknowledgments

This research was supported by grant R01AI090810 by the National Institute of Allergy and Infectious Diseases and grant S10OD016226, Office of the Director, National Institutes of Health and the American Lebanese Syrian Associated Charities (ALSAC). We thank Tom Mohaupt, Jennings Payne, Kellen Thuo, and Warner Turner (Radiation Safety Division, St. Jude Children’s Research Hospital, Memphis, TN) for their help in determining the total and specific activity of the radiolabeled compound. We thank Dr. Feng Yin and Dr. James T. Dalton (GTx Inc., Memphis, TN) for the opportunity to use their sample oxidation equipment.

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Correspondence to Bernd Meibohm.

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All animal experiments were conducted in accordance with the Animal Welfare Act and the Public Health Service Policy on Humane Care and Use of Laboratory Animals. The study protocol was approved by the Institutional Animal Care and Use Committee and the Radiation Safety Committee of the University of Tennessee Health Science Center.

Conflict of Interest

J.L., R.E.L., and B.M. disclose intellectual property rights ownership associated with the spectinamide series.

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Madhura, D.B., Trivedi, A., Liu, J. et al. Tissue Penetration of a Novel Spectinamide Antibiotic for the Treatment of Tuberculosis. AAPS J 18, 788–791 (2016). https://doi.org/10.1208/s12248-016-9900-7

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