Optimized LC-MS/MS quantification of tuberculosis drug candidate macozinone (PBTZ169), its dearomatized Meisenheimer Complex and other metabolites, in human plasma and urine

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

“…Therefore, an increasing number of quantitative analyses of second-line anti-TB drugs and their metabolites have been established to optimize the treatment of TB, especially MDR-TB or first-line drugs TB-resistant [ 56 ]. Table 2 [ 37 , 40 , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] ] summarizes these LC-MS bioassay methods.…”

“…First, they observed that H 2 PBTZ was the most prevalent species circulating in plasma. Second, the low concentration of analytes in urine suggested a high rate of metabolism prior to renal excretion [ 68 ]. Lee et al.…”

“…Significantly, capturing endogenous metabolites together with anti-TB drugs and their metabolites may expand the use of the developed bioassay for subsequent applications. Typical examples include evaluation of toxicity [ 27 ] and individualization of treatment dosage, especially for new analogs [ 68 , 121 ], that could be directed by endogenous compounds [ 122 ].…”

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

“…Desfontaine et al reported an optimized LC-MS/MS method for quantification of the Meisenheimer complex and other metabolites of PBTZ169. 124 Apart from dearomatization, the metabolism of PBTZ169 is complicated, especially due to hydroxylation reactions of the cyclohexyl group of the side chain. 125…”

“…Desfontaine et al reported an optimized LC-MS/MS method for quantification of the Meisenheimer complex and other metabolites of PBTZ169. 124 Apart from dearomatization, the metabolism of PBTZ169 is complicated, especially due to hydroxylation reactions of the cyclohexyl group of the side chain. 125 An up-to-date in-depth computational analysis and evaluation of physicochemical descriptors and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of a total of 41.500 published DprE1 inhibitors against M. tuberculosis including BTZs can be found in the literature.…”