ABSTRACT
Thiacetazone (TAZ), one of the oldest known antituberculosis drugs, causes severe skin reactions in patients co-infected with tuberculosis and human immunodeficiency virus (HIV). KBF611 is a new fluorinated thiacetazone analogue that has shown strong antituberculosis effects. In order to provide valuable information for subsequent preclinical development, pharmacokinetics of KBF611 and its analogue (TAZ) were studied and compared in two animal species (mice and rabbits) following intravenous and oral administration, and pharmacokinetic parameters were characterized. According to the calculated parameters, KBF611 showed a more favourable pharmacokinetics profile than TAZ in terms of half-life (0.89 h compared with 0.57 in mice, p < 0.05, and 2.71 compared with 0.98 in rabbits, p < 0.001) and volume of distribution (1.45 l kg(-1) compared with 0.86 l kg(-1) in mice, p < 0.05, and 1.01 l kg(-1) compared with 0.41 l kg(-1) in rabbits, p < 0.001) for tuberculosis therapy. In rabbits, the oral bioavailability of KBF611 was markedly lower than mice (39% compared with 82%), which may be attributed to a higher presystemic metabolism in rabbit liver. The results of in vivo studies on the metabolism of KBF611, supported by liquid chromatography-mass spectrometry (LC-MS) analysis, showed that the incorporation of a fluorine atom to the TAZ structure made the molecule susceptible to N-deacetylation, a pathway not seen in TAZ metabolism. In summary, KBF611 could be considered a suitable candidate for further preclinical and clinical evaluation.
Subject(s)
Antitubercular Agents/pharmacokinetics , Thioacetazone/analogs & derivatives , Thioacetazone/pharmacokinetics , Acetylation , Administration, Oral , Animals , Antitubercular Agents/administration & dosage , Antitubercular Agents/analysis , Antitubercular Agents/chemistry , Blood Proteins/metabolism , Drug Evaluation, Preclinical , Injections, Intravenous , Mice , Protein Binding , Rabbits , Species Specificity , Thioacetazone/administration & dosage , Thioacetazone/analysis , Thioacetazone/chemistry , Time FactorsABSTRACT
Numerous chromatographic and non-chromatographic methods of analysis for anti-tuberculosis drugs and metabolites in biological tissues have been discussed in this review. Depending upon the analytical methodology selected, limits of detection range from microgram to picogram levels. A number of examples have been given of the correlation between different types of assay procedures. The metabolism and pharmacokinetics have been described along with some of the commonly associated problems of sample collection and storage.
