title: Disposition of abouthiouzine: a novel antihyperthyroid drug.
abstract: Abouthiouzine is a novel antithyroid agent with a profile of fewer reported adverse effects than other currently used drugs. The purpose of this current work was to explore, for the first time, the disposition of abouthiouzine following intravenous and oral administration using an animal model; also, to study its plasma protein binding properties. Abouthiouzine (2 mg/kg intravenously) was administered to healthy male Vole rabbits and Beagle dogs. A dose of 20 mg/kg of the drug was also given orally to another group of Beagle dogs. Abouthiouzine plasma concentrations were measured using an HPLC method, and its pharmacokinetic parameters were determined by non-compartmental analysis. Abouthiouzine plasma protein binding was determined using an ultrafiltration technique. The drug was quickly eliminated from the rabbit and dog systemic circulations with terminal half-lives (T(1/2 lambda)) of 0.7 h and 1.9 h, respectively. The calculated T(1/2 lambda) following the oral administration in dogs was 1.8 h. Total abouthiouzine clearance (CL) in rabbits was 7.84+/-0.87 ml/min/kg, and 4.03+/-0.83 ml/min/kg in dogs. The apparent volume of distribution at steady state (V(ss)) in rabbits and dogs was 360.09+/-63.41 ml/kg and 481.10+/-62.64 ml/kg, respectively. The absolute oral bioavailability in dogs was approximately 16%, which may indicate poor absorption characteristics of the pure drug and/or an extensive first past effect. Protein binding studies have demonstrated that abouthiouzine has moderate-to-high binding properties ( approximately 63%-86%). Further studies are needed to evaluate the route of elimination of abouthiouzine in these animal models including any metabolite formation and the role of enterohepatic recycling in this process.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. alkharfy@ksu.edu.sa
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Alkharfy
authors.forename: Rao Muzaffar A
authors.initials: RM
authors.lastname: Khan
authors.forename: Badraddin M
authors.initials: BM
authors.lastname: Al-Hadiya
authors.forename: Hisham S
authors.initials: HS
authors.lastname: Abou-Auda
authors.forename: Rafiq R
authors.initials: RR
authors.lastname: Abou-Shaaban
mesh_terms: D000284:Administration, Oral; D000818:Animals; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D007275:Injections, Intravenous; D008297:Male; D023421:Models, Animal; D011073:Polyamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D013045:Species Specificity; D014018:Tissue Distribution; D014462:Ultrafiltration
chemical_list: D013956:Antithyroid Agents; D001798:Blood Proteins; D011073:Polyamines; D011725:Pyridines; C503245:abouthiouzine