02394nas a2200157   4500008004100000022001400041245010600055210006900161260000800230300001400238490000700252520180100259100002502060700002302085856012802108       2023                        eng d  a2163-830600aPhysiologically-based pharmacokinetic model for tuberculosis drug disposition at extrapulmonary sites0 aPhysiologicallybased pharmacokinetic model for tuberculosis drug  cSEP  a1274-12840 v123 a<p>
	Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the pharmacokinetics of EPTB therapy are not as well studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node, the most commonly affected sites of EPTB. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the following four first-line anti-TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use reported plasma concentration kinetics data to estimate model parameters for each drug and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data, and reported pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) for the drugs. The model also predicts ethambutol, isoniazid, and pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although rifampicin and isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of ethambutol and pyrazinamide are lower than their critical concentrations at most EPTB sites.</p>
1 aRamachandran, Aparna1 aGadgil, Chetan, J.  uhttps://library.ncl.res.in/content/physiologically-based-pharmacokinetic-model-tuberculosis-drug-disposition-extrapulmonary02084nas a2200289   4500008004100000022001400041245009100055210006900146260000800215300001600223490000700239520114900246100001701395700001901412700003301431700002201464700001901486700001601505700002501521700001701546700002101563700002301584700002601607700001601633700002501649856012001674       2025                        eng d  a0022-262300aMycobacteria-specific prodrug to overcome phenotypic AMR in mycobacterium tuberculosis0 aMycobacteriaspecific prodrug to overcome phenotypic AMR in mycob  cDEC  a24935-249520 v683 a<p>
	Most front-line tuberculosis (TB) drugs are ineffective against hypoxic nonreplicating Mycobacterium tuberculosis (Mtb), largely due to poor permeability, leading to reduced drug accumulation and target engagement. To overcome this phenotypic antimicrobial resistance (AMR), we developed nitroheteroaryl prodrugs for Moxifloxacin (MXF), a front-line TB drug. These prodrugs are activated by bacterial nitroreductases (NTR), which are overexpressed in hypoxic Mtb. NTR-mediated electron transfer and protonation facilitate rapid cleavage of the protective group, releasing active MXF. The lead prodrug exhibited comparable efficacy to MXF in replicating Mtb and significantly enhanced lethality in nonreplicating Mtb. Drug accumulation studies confirmed a modest but significant increase in MXF levels in nonreplicating Mtb treated with the prodrug, suggesting improved permeability. A mathematical model integrating growth and drug-killing kinetics further elucidated how permeability differences impact lethality. Together, these findings highlight enzyme-activated prodrugs as a promising strategy to address phenotypic AMR in Mtb</p>
1 aKumar, Anand1 aBirua, Shalini1 aMallojjala, Sharath, Chandra1 aMukherjee, Piyali1 aSingh, Samsher1 aKaul, Grace1 aRamachandran, Aparna1 aAkhir, Abdul1 aChopra, Sidharth1 aGadgil, Chetan, J.1 aHirschi, Jennifer, S.1 aSingh, Amit1 aChakrapani, Harinath  uhttps://library.ncl.res.in/content/mycobacteria-specific-prodrug-overcome-phenotypic-amr-mycobacterium-tuberculosis