Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging

Vincent P. DeMarco, Alvaro A. Ordonez, Mariah Klunk, Brendan Prideaux, Hui Wang, Zhang Zhuo, Peter J. Tonge, Robert F. Dannals, Daniel P. Holt, Carlton K.K. Lee, Edward A. Weinstein, Véronique Dartois, Kelly E. Dooley, Sanjay K. Jain

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Information about intralesional pharmacokinetics (PK) and spatial distribution of tuberculosis (TB) drugs is limited and has not been used to optimize dosing recommendations for new or existing drugs. While new techniques can detect drugs and their metabolites within TB granulomas, they are invasive, rely on accurate resection of tissues, and do not capture dynamic drug distribution in the tissues of interest. In this study, we assessed the in situ distribution of 11C-labeled rifampin in live, Mycobacterium tuberculosis-infected mice that develop necrotic lesions akin to human disease. Dynamic positron emission tomography (PET) imaging was performed over 60 min after injection of [11C]rifampin as a microdose, standardized uptake values (SUV) were calculated, and noncompartmental analysis was used to estimate PK parameters in compartments of interest. [11C]rifampin was rapidly distributed to all parts of the body and quickly localized to the liver. Areas under the concentration-time curve for the first 60 min (AUC0-60) in infected and uninfected mice were similar for liver, blood, and brain compartments (P > 0.53) and were uniformly low in brain (10 to 20% of blood values). However, lower concentrations were noted in necrotic lung tissues of infected mice than in healthy lungs (P = 0.03). Ex vivo two-dimensional matrix-assisted laser desorption ionization (MALDI) imaging confirmed restricted penetration of rifampin into necrotic lung lesions. Noninvasive bioimaging can be used to assess the distribution of drugs into compartments of interest, with potential applications for TB drug regimen development.

Original languageEnglish (US)
Pages (from-to)5768-5774
Number of pages7
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number9
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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