Introduction Tuberculosis is one of the most common infectious dis- eases known to man. About 32% of the world’s popula- tion, or 1.86 billion people, are infected with tuberculosis. Every year, approximately 8 million of these develop active tuberculosis, and almost 2 million of them die from the disease (Frieden et al. 2003). With the global spread of human immunodeiciency virus (HIV), similar increases in tuberculosis incidence rates and mortality are to be feared (Cock & Chaisson 1999). Moreover, there has been a recent and disturbing increase in the number of tuberculosis cases caused by organisms that are resistant to the irst-line drugs isoniazid, rifampicin, ethambutol, streptomycin and pyrazinamide. herefore, the necessity for new drugs against Mycobacterium tuberculosis is well documented (Duncan 2003). hiacetazone (TAZ, 4-acetamido benzaldehydethi- osemicarbazone) (Figure 1), one of the oldest known antituberculosis drugs, is an inexpensive bacteriostatic agent that is widely used in combination with isoniazide in developing countries. However, in co-infection of tuberculosis with HIV, severe skin reactions have been reported (Dukes et al. 1992; Ipuge et al. 1995). Recent Xenobiotica, 2009, 1–10, Early Online Address for Correspondence: S. Dadashzadeh, Department of Pharmaceutics, Biopharmacy and Pharmacokinetic Division, School of Pharmacy, Shaheed Beheshti Medical University, PO Box 14155-6153, Tehran, Iran. Tel: 98-21-8820070. Fax: 98-21-88209620. E-mail: Sdadashzadeh@sbmu.ac.ir RESEARCH ARTICLE Preclinical pharmacokinetics of KBF611, a new antituberculosis agent in mice and rabbits, and comparison with thiacetazone F.M. Shahab 1 , F. Kobarfard 2,4 , B. Shafaghi 3,4 , and S. Dadashzadeh 1,4 1 Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, 2 Department of Medicinal Chemistry, 3 Department of Toxicology and Pharmacology, School of Pharmacy, Shaheed Beheshti Medical University, Tehran, Iran, and 4 Pharmaceutical Sciences Research Centre, Shaheed Beheshti Medical University, Tehran, Iran Abstract 1. Thiacetazone (TAZ), one of the oldest known antituberculosis drugs, causes severe skin reactions in patients co-infected with tuberculosis and human immunodeiciency virus (HIV). KBF611 is a new luori- nated thiacetazone analogue that has shown strong antituberculosis efects. 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. 2. According to the calculated parameters, KBF611 showed a more favourable pharmacokinetics proile 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 attrib- uted 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 luorine atom to the TAZ structure made the molecule susceptible to N-deacetylation, a pathway not seen in TAZ metabolism. 3. In summary, KBF611 could be considered a suitable candidate for further preclinical and clinical evaluation. Keywords: KBF611; thiacetazone; pharmacokinetics; tuberculosis (Received 18 September 2009; revised 02 November 2009; accepted 04 November 2009) ISSN 0049-8254 print/ISSN 1366-5928 online © 2009 Informa UK Ltd DOI: 10.3109/00498250903461411 http://www.informahealthcare.com/xen Xenobiotica Downloaded from informahealthcare.com by University of California Davis For personal use only.