title: Pharmacokinetics, in-situ absorption and protein binding studies of a new neuroleptic agent centbutindole in rats.
abstract: The present study reports the absorption kinetics, plasma protein binding and pharmacokinetic profile of the centbutindole (I) after i.v. and oral dosing in rats. In addition, an in-situ absorption study was carried out using a closed-loop technique at pH 2.6 and 7.4. The rate of absorption at pH 2.6 was 5-fold less compared to that observed at pH 7.4. In-vitro and in-vivo protein binding (ultra filtration technique) was independent of substrate concentration over a range of 1.25-10.0 microg/ml. Pharmacokinetic parameters of I were determined in male rats after administering a single 4 mg/kg oral dose and 2 mg/kg intravenous dose. The peak serum concentration of I was found to be 50.1 ng/ml at 30 min after oral administration followed by a secondary Cmax of 43.2 ng/ml at 180 min. For the hydroxy metabolite (II), a Cmax of 6.4 ng/ml was measured at 360 min after oral administration of I. After oral dosing an irregular concentration-time profile with secondary peaks was observed for both I and II. The terminal half-lives for I and II after oral dosing were 163 and 263 min, respectively. After intravenous dosing, the levels of I decreased biexponentially with a distribution (t(1/2) alpha) and elimination (t(1/2) beta) half-lives of 5.7 and 128 min, respectively. Comparison of the AUC after oral and intravenous dosing of I indicates that only about 24% of the oral dose reaches the systemic circulation. The limited bioavailability can either be due to the poor solubility of the compound and/or extensive first pass metabolism in the gastrointestinal (GI) tract. Co-administration of polyethylene glycol (PEG) at oral dosing improves solubilization and increases bioavailability.
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow 226001, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Issar
authors.forename: Shio K
authors.initials: SK
authors.lastname: Singh
authors.forename: Bhrameshwar
authors.initials: B
authors.lastname: Mishra
authors.forename: Ram C
authors.initials: RC
authors.lastname: Gupta
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D011719:Pyrazines; C039923:centbutindole