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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives
ACS Infectious Diseases, Volume 1, No. 5, Year 2015
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Description
Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we revisit long-standing paradigms and offer pharmacokinetic explanations for the apparent disconnect between in vitro activity and clinical impact. We show substantial host-mediated conversion of prodrug pyrazinamide (PZA) to the active form, pyrazinoic acid (POA), in TB patients and in animal models. We demonstrate favorable penetration of this pool of circulating POA from plasma into lung tissue and granulomas, where the pathogen resides. In standardized growth inhibition experiments, we show that POA exhibits superior in vitro potency compared to PZA, indicating that the vascular supply of host-derived POA may contribute to the in vivo efficacy of PZA, thereby reducing the apparent discrepancy between in vitro and in vivo activity. However, the results also raise the possibility that subinhibitory concentrations of POA generated by the host could fuel the emergence of resistance to both PZA and POA. In contrast to widespread expectations, we demonstrate good oral bioavailability and exposure in preclinical species in pharmacokinetic studies of oral POA. Baseline exposure of oral POA can be further increased by the xanthine oxidase inhibitor and approved gout drug allopurinol. These promising results pave the way for clinical investigations of oral POA as a therapeutic alternative or an add-on to overcome PZA resistance and salvage this essential TB drug. © 2015 American Chemical Society.
Authors & Co-Authors
Via, L. E.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Savic, Rada M.
United States, San Francisco
University of California, San Francisco
Weiner, Danielle M.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Zimmerman, Matthew D.
United States, Newark
Public Health Research Institute
Prideaux, Brendan
United States, Newark
Public Health Research Institute
O'Brien, Paul
United States, Newark
Public Health Research Institute
Eum, Seokyong
South Korea, Changwon
International Tuberculosis Research Center
Lee, Myungsun
South Korea, Changwon
International Tuberculosis Research Center
Dutta, Noton K.
United States, Baltimore
Johns Hopkins School of Medicine
Shim, Tae-sun
South Korea, Seoul
Asan Medical Center
Cho, Jeongsu
South Korea, Busan
Pusan National University Hospital
Kim, Wooshik
South Korea, Seoul
National Medical Center
Karakousis, Petros C.
United States, Baltimore
Johns Hopkins School of Medicine
Lenaerts, Anne J.
United States, Fort Collins
Colorado State University
Nuermberger, Eric L.
United States, Baltimore
Johns Hopkins School of Medicine
Barry, Clifton Earl
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Dartois, Véronique A.
United States, Newark
Public Health Research Institute
Statistics
Citations: 65
Authors: 17
Affiliations: 10
Identifiers
Doi:
10.1021/id500028m
ISSN:
23738227
Research Areas
Health System And Policy
Infectious Diseases