Preclinical pharmacokinetic profiling of IQG-607, a potential oral metallodrug to treat tuberculosis

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Adilio da S. Dadda, Valnês S. Rodrigues-Junior, Fernando Carreño, Guilherme O. Petersen, Antônio F.M. Pinto, Pedro F. Dalberto, Nathalia D.M. Sperotto, Kenia Pissinate, Cristiano V. Bizarro, Pablo Machado, Maria M. Campos, Teresa Dalla Costa, Diógenes S. Santos, Luiz A. Basso
IQG-607 is an analog of isoniazid with anti-tuberculosis activity. This work describes the development and validation of an HPLC method to quantify pentacyano(isoniazid)ferrate(II) compound (IQG-607) and the pharmacokinetic studies of this compound in mice. The method showed linearity in the 0.5–50μg/mL concentration range (r=0.9992). Intra- and inter-day precision was <5%, and the recovery ranged from 92.07 to 107.68%. IQG-607 was stable in plasma for at least 30days at −80°C and, after plasma processing, for 4h in the auto-sampler maintained on ice (recovery >85%). The applicability of the method for pharmacokinetic studies was determined after intravenous (i.v.) and oral (fasted and fed conditions) administration to mice. IQG-607 levels in plasma were quantified at time points for up to 2.5h. A short half-life (t1/2) (1.14h), a high clearance (CL) (3.89L/h/kg), a moderate volume of distribution at steady state (Vdss) of 1.22L/kg, were observed after i.v. (50mg/kg) administration. Similar results were obtained for oral administration (250mg/kg) under fasted and fed conditions. The oral bioavailability (F), approximately 4%, was not altered by feeding. Plasma protein binding was 88.87±0.9%. The results described here provide novel insights into a pivotal criterion to warrant further efforts to be pursued towards attempts to translate this chemical compound into a chemotherapeutic agent to treat TB.

Graphical abstract

http://ift.tt/2zvPoiE