A physiology-based pharmacokinetic model describing the disposition of a novel selective anxiolytic drug afobazole and its metabolites in rats.
Viglinskaya A.O., Kolyvanov G.B., Mesonzhnik N.V., Baranov P.A., Litvin A.A., Zherdev V.P., Rodchenkov G.M.
(1)State Zakusov Research Institute of Pharmacology, RAMS. (2) Antidoping centre, Moscow, Russian Federation.
Objectives: The purpose of this study was to model the pharmacokinetics of a novel selective anxiolytic drug afobazole [2-(2-morpholinoethylthio)-5-ethoxybenzimidazole dihydrocloride] and its metabolites in rats using physiology-based (PBPK) modeling approaches.
Methods: We examined in vivo metabolism and the pharmacokinetics of Afobazole and its metabolites in rats as a component of its preclinical development by a validated HPLC/MS/MS method. 160 male Wistar rats were randomly assigned to treatment groups and received either an i.p. and a p.o. dose of Afobazole at a dose level of 25 mg/kg. The model was constructed using the Windows version of WinSAAM software, a general equation-solving package that has been developed. Thus, the physiological processes responsible for afobazole pharmacokinetic characteristics were assessed.
Results: Afobazole demonstrated a large-scale volume of distribution (range, 7.11-23.5 l/kg), a rapid clearance (range, 15.04-30.9 l/hr/kg), and a terminal half-life 0.33 h (for its metabolites ranging from 0.40 to 0.44 h) after i.p. dosage. Afobazole is characterized by the expressed ability to penetrate organs and tissues. Afobazole is rapidly absorbed, cleared and extensively metabolized in rats.
Conclusions: PK model of a novel selective anxiolytic drug afobazole and its metabolites based on physiological modeling adequately described the observed plasma and organ concentration data and the estimated parameters are consistent with the previously available data.