title: Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging.
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 (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 (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.
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: DeMarco
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Ordonez
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mariah
authors.initials: M
authors.lastname: Klunk
authors.affiliation: Public Health Research Institute Center, New Jersey Medical School-Rutgers, Newark, New Jersey, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Prideaux
authors.affiliation: Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhuo
authors.affiliation: Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Carlton K K
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Weinstein
authors.affiliation: Public Health Research Institute Center, New Jersey Medical School-Rutgers, Newark, New Jersey, USA.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA sjain5@jhmi.edu.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D005260:Female; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D049268:Positron-Emission Tomography; D012293:Rifampin / Q000493:pharmacokinetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014376:Tuberculosis / Q000378:metabolism / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D012293:Rifampin