Radiosynthesis and Bioimaging of the Tuberculosis Chemotherapeutics Isoniazid, Rifampicin and Pyrazinamide in Baboons

Abstract

The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [11C]CH3I to label RIF, and [11C]HCN to label INH and PZA. Following i.v. administration, INH, PZA, RIF and/or their radiolabeled metabolites clear rapidly from many tissues, however INH, PZA and/or their metabolites accumulate in the bladder while RIF and/or its metabolites accumulates in the liver and gall bladder, consistent with the routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood-brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth. The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain, and pave the way for imaging the distribution of the pathogen in vivo.

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

“…Given that rifampin does not have a fluorine atom, carbon-11 was chosen so that the radiolabeled atom could be introduced into the molecule without altering its chemical structure, which could affect drug distribution. In addition, the position of the radiolabel was chosen to ensure that it would be retained on the molecule even if the drug were metabolized in the liver (15). This was not the case for MALDI utilized in this study, which captured only rifampin.…”

“…[ 11 C]rifampin was synthesized at the Johns Hopkins PET Center using a modification of the methods described by Liu et al (15). Briefly, [ 11 C]rifampin was synthesized by standard solution chemistry using […”

Noninvasive Determination of 2-[ 18 F]-Fluoroisonicotinic Acid Hydrazide Pharmacokinetics by Positron Emission Tomography in Mycobacterium tuberculosis-Infected Mice

“…The pathogen-specific metabolism and accumulation of INH makes it an attractive imaging probe with the potential to both detect bacteria and yield PK data in situ (15). We recently reported the bioimaging of [ 11 C]-INH and two other carbon-11-labeled TB therapeutics in healthy baboons (20). We have now extended this work to the evaluation of a fluorine-18 analog of INH, which also has the advantage of translation to clinical settings (25).…”

“…New techniques, such as matrix-assisted laser desorption ionization (MALDI) mass spectrometry, have the power to detect drugs and their metabolites within a granuloma (32) but are invasive and rely on accurate resection of tissue. Positron emission tomography (PET) is a noninvasive alternative to determine the characteristics of drug absorption, distribution, and elimination in both clinical and preclinical settings (8,12,20). The pathogen-specific metabolism and accumulation of INH makes it an attractive imaging probe with the potential to both detect bacteria and yield PK data in situ (15).…”

Subcellular Partitioning and Intramacrophage Selectivity of Antimicrobial Compounds against Mycobacterium tuberculosis

“…Tissue-level accumulation, especially in lung and spleen, has been demonstrated for established (20,21) and emerging (22,23) antitubercular compounds and is believed to enhance their efficacy against M. tuberculosis. We sought to determine if ACA compounds accumulate within bone marrow-derived macrophages (BMDM), and if so, the extent to which such accumulation depends on acidic compartments.…”