PMID- 30711150
OWN - NLM
STAT- MEDLINE
DCOM- 20190701
LR  - 20200309
IS  - 1873-281X (Electronic)
IS  - 1472-9792 (Print)
IS  - 1472-9792 (Linking)
VI  - 114
DP  - 2019 Jan
TI  - Comparative pharmacokinetics of spectinamide 1599 after subcutaneous and 
      intrapulmonary aerosol administration in mice.
PG  - 119-122
LID - S1472-9792(18)30413-X [pii]
LID - 10.1016/j.tube.2018.12.006 [doi]
AB  - Spectinamides are a novel series of spectinomycin analogs being developed for the 
      treatment of tuberculosis. Intrapulmonary aerosol (IPA) administration of lead 
      spectinamide 1599 has previously been shown to be more efficacious than 
      subcutaneous (SC) administration at comparable doses. The objective of the 
      current study was to characterize the disposition of 1599 in plasma and lungs in 
      mice in order to provide a potential rationale for the observed efficacy 
      differences. 200 mg/kg of 1599 was administered to healthy BALB/c mice by SC 
      injection or by IPA delivery. Plasma and major organs were collected at specified 
      time points until 8 h after dosing. Drug concentrations were measured by LC-MS/MS 
      and analyzed by noncompartmental pharmacokinetic analysis. 1599 demonstrated 
      rapid absorption into plasma after IPA and SC administration, resulting in very 
      similar plasma exposure for both routes. In contrast, drug exposure in the lungs 
      was 48 times higher following IPA as compared to SC administration, which is 
      highly desirable as the lungs are the main site of infection in pulmonary TB. The 
      higher local exposure in the lungs is likely the basis for the increased efficacy 
      after IPA compared to SC administration. Overall, this study supports the 
      pulmonary route as a potential pathway for the treatment of tuberculosis with 
      1599.
CI  - Copyright (c) 2018. Published by Elsevier Ltd.
FAU - Rathi, Chetan
AU  - Rathi C
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Tennessee Health Science Center, Memphis, TN 38163, USA.
FAU - Lukka, Pradeep B
AU  - Lukka PB
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Tennessee Health Science Center, Memphis, TN 38163, USA.
FAU - Wagh, Santosh
AU  - Wagh S
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Tennessee Health Science Center, Memphis, TN 38163, USA.
FAU - Lee, Richard E
AU  - Lee RE
AD  - Department of Chemical Biology, St. Jude Children's Research Hospital, Memphis, 
      TN 38105, USA.
FAU - Lenaerts, Anne J
AU  - Lenaerts AJ
AD  - Mycobacterial Research Laboratories, Department of Microbiology, Colorado State 
      University, Fort Collins, CO 80523, USA.
FAU - Braunstein, Miriam
AU  - Braunstein M
AD  - Department of Microbiology and Immunology, University of North Carolina, Chapel 
      Hill, NC 27599, USA.
FAU - Hickey, Anthony
AU  - Hickey A
AD  - Discovery Science and Technology, RTI International, Durham, NC 27709, USA.
FAU - Gonzalez-Juarrero, Mercedes
AU  - Gonzalez-Juarrero M
AD  - Mycobacterial Research Laboratories, Department of Microbiology, Colorado State 
      University, Fort Collins, CO 80523, USA.
FAU - Meibohm, Bernd
AU  - Meibohm B
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: 
      bmeibohm@uthsc.edu.
LA  - eng
GR  - R01 AI090810/AI/NIAID NIH HHS/United States
GR  - R01 AI120670/AI/NIAID NIH HHS/United States
GR  - S10 OD016226/OD/NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181231
PL  - Scotland
TA  - Tuberculosis (Edinb)
JT  - Tuberculosis (Edinburgh, Scotland)
JID - 100971555
RN  - 0 (Antitubercular Agents)
RN  - 0 (spectinamide 1599)
RN  - 93AKI1U6QF (Spectinomycin)
SB  - IM
MH  - Administration, Inhalation
MH  - Animals
MH  - Antitubercular Agents/administration & dosage/*pharmacokinetics
MH  - Biological Availability
MH  - Drug Evaluation, Preclinical/methods
MH  - Female
MH  - Injections, Subcutaneous
MH  - Lung/metabolism
MH  - Mice, Inbred BALB C
MH  - Spectinomycin/administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - Tuberculosis/drug therapy/*metabolism
PMC - PMC6362843
MID - NIHMS1517919
OTO - NOTNLM
OT  - Antibiotics
OT  - Inhalation
OT  - Pharmacokinetics
OT  - Tissue exposure
OT  - Tuberculosis
EDAT- 2019/02/04 06:00
MHDA- 2019/07/02 06:00
PMCR- 2020/01/01
CRDT- 2019/02/04 06:00
PHST- 2018/09/30 00:00 [received]
PHST- 2018/12/26 00:00 [revised]
PHST- 2018/12/30 00:00 [accepted]
PHST- 2019/02/04 06:00 [entrez]
PHST- 2019/02/04 06:00 [pubmed]
PHST- 2019/07/02 06:00 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - S1472-9792(18)30413-X [pii]
AID - 10.1016/j.tube.2018.12.006 [doi]
PST - ppublish
SO  - Tuberculosis (Edinb). 2019 Jan;114:119-122. doi: 10.1016/j.tube.2018.12.006. Epub 
      2018 Dec 31.