title: Tissue Penetration of a Novel Spectinamide Antibiotic for the Treatment of Tuberculosis.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Suite 444, Memphis, Tennessee, 38163, USA.
authors.forename: Dora Babu
authors.initials: DB
authors.lastname: Madhura
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Suite 444, Memphis, Tennessee, 38163, USA.
authors.forename: Ashit
authors.initials: A
authors.lastname: Trivedi
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
authors.forename: Jiuyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Boyd
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Suite 444, Memphis, Tennessee, 38163, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Loveless
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Suite 444, Memphis, Tennessee, 38163, USA. bmeibohm@uthsc.edu.
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D000198:Spectinomycin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D014376:Tuberculosis
chemical_list: D000900:Anti-Bacterial Agents; D000198:Spectinomycin
keywords: biodistribution; mass balance; pharmacokinetics; spectinamide; tuberculosis