Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons
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 [{sup 11}C]CH{sub 3}I to label RIF and [{sup 11}C]HCN to label INH and PZA. Following iv administration, INH, PZA, RIF, and/or their radiolabeled metabolites clear rapidly from many tissues; however, INH, PZA, and/or their radiolabeled metabolites accumulate in the bladder while RIF and/or its radiolabeled metabolites accumulates in the liver and gall bladder, consistent with the known 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 of Mycobacterium tuberculosis (MTB). 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.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Organization:
- USDOE SC OFFICE OF SCIENCE (SC)
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 1041491
- Report Number(s):
- BNL-91382-2010-JA; JMCMAR; R&D Project: MO085; NIH grant AI084189; KP1602010; TRN: US1202659
- Journal Information:
- Journal of Medicinal Chemistry, Vol. 53, Issue 7; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS
BABOONS
BLADDER
BLOOD-BRAIN BARRIER
BRAIN
CARBON 11
DISTRIBUTION
EXCRETION
IN VIVO
ISONIAZID
LIVER
METABOLITES
MYCOBACTERIUM TUBERCULOSIS
PATHOGENS
POSITRONS
TOMOGRAPHY
TUBERCULOSIS
baboon
tuberculosis
brain
mycobacterium tuberculosis
radiolabeled metabolites
carbon-11