Determination of [ ¹¹ C]Rifampin Pharmacokinetics within Mycobacterium tuberculosis-Infected Mice by Using Dynamic Positron Emission Tomography Bioimaging

Abstract

e 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 11 C-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 [ 11 C]rifampin as a microdose, standardized uptake values (SUV) were calculated, and noncompartmental analysis was used to estimate PK parameters in compartments of interest. [11 C]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 (AUC 0 -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.

Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9

“…The presence of multiple different pulmonary lesions in C3HeB/FeJ mice was described recently ( Irwin et al, 2015 ), but cavitation was a rare event under the conditions evaluated. Because several TB drugs with differing physicochemical properties have been shown to partition differently into these lesions in a manner similar to observations in humans and/or rabbits ( DeMarco et al, 2015 ; Irwin et al, 2016 ; Kjellsson et al, 2012 ; Lanoix et al, 2016b ; Prideaux et al, 2015 ; Weinstein et al, 2012 ), and because the activity of some drugs might be modulated by conditions within large caseous lesions ( Lanoix et al, 2015 , 2016a ), the more tractable and economical C3HeB/FeJ mouse model that exhibits these multiple lesion types provides an important new tool for TB drug development research.…”

The biodistribution of 5-[18F]fluoropyrazinamide in Mycobacterium tuberculosis-infected mice determined by positron emission tomography

“…Dynamic PET can provide multi-compartment analyses at multiple time points, allowing the characterization of radiolabeled drug concentrations in multiple tissues simultaneously. Previous studies with whole-body PET bioimaging in murine models of TB have provided valuable information about the pharmacokinetics of the first-line TB drugs isoniazid (2-[ 18 F]fluoroisonicotinic acid hydrazide, [ 26 ]) and rifampin ( 11 C-rifampin, [ 27 ]).…”

Targeting of vascular adhesion protein-1 by positron emission tomography visualizes sites of inflammation in Borrelia burgdorferi-infected mice

“…Another interesting group of infection-selective radiotracers is the labeled siderophores, which have shown promising results for the imaging of infection caused by Aspergillus fumigatus [ 41 ]. Previous studies on imaging of Mycobacterium tuberculosis infections have also identified potential radiopharmaceuticals that may replace 18 F-FDG in the future [ 42 , 43 ]. Nevertheless, investigations on infection- and inflammation-selective radiopharmaceuticals are still in their infancy, and novel approaches need to be evaluated in different model systems.…”