Comparative pharmacokinetics of spectinamide 1599 after subcutaneous and intrapulmonary aerosol administration in mice.
Antibiotics
Inhalation
Pharmacokinetics
Tissue exposure
Tuberculosis
Journal
Tuberculosis (Edinburgh, Scotland)
ISSN: 1873-281X
Titre abrégé: Tuberculosis (Edinb)
Pays: Scotland
ID NLM: 100971555
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
30
09
2018
revised:
26
12
2018
accepted:
30
12
2018
entrez:
4
2
2019
pubmed:
4
2
2019
medline:
2
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30711150
pii: S1472-9792(18)30413-X
doi: 10.1016/j.tube.2018.12.006
pmc: PMC6362843
mid: NIHMS1517919
pii:
doi:
Substances chimiques
Antitubercular Agents
0
spectinamide 1599
0
Spectinomycin
93AKI1U6QF
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
119-122Subventions
Organisme : NIAID NIH HHS
ID : R01 AI090810
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI120670
Pays : United States
Organisme : NIH HHS
ID : S10 OD016226
Pays : United States
Informations de copyright
Copyright © 2018. Published by Elsevier Ltd.
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