title: Pharmacokinetics, dose proportionality and permeability of S002-333 and its enantiomers, a potent antithrombotic agent, in rabbits.
abstract: 1. S002-333 [(2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide)] is a novel and potent antithrombotic active agent. The present work investigates the pharmacokinetics, bioavailability, dose proportionality and permeability of the racemate, S002-333 in male New Zealand White (NZW) rabbits. 2. Rabbits were administered single intravenous (i.v.) (2 mg/kg) and three oral doses of 10, 20 and 40 mg/kg of S002-333, respectively, at different occasions to evaluate dose proportionality. Serial blood samples were collected and analyzed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Since S002-333 is a racemate consisting of S004-1032 (R) and S007-1558 (S), same samples were analyzed using a chiralcel column so as to evaluate the respective enantiomers. 3. The peak plasma concentration, after oral administration, occurred at ∼10 h post-dose. The clearance (CL) and volume of distribution (Vd) after i.v. dose were found to be 3.05 ± 0.09 l/h/kg and 6.73 ± 1.16 l/kg, respectively. The absolute oral bioavailability of S002-333 was 16.32%, whereas it was 6.62 and 5.90% for R- and S-enantiomers, respectively. The absolute bioavailability of 10, 20 and 40 mg/kg doses were found to be 27.91, 14.39 and 16.91%, respectively. The PAMPA (parallel artificial membrane permeability assay) assay shows that S002-333 has a low-passive permeability at gastric and intestinal environment. 4. In conclusion, S002-333 has low-passive permeability, low CL and large Vd. The R-enantiomer has a "slightly" greater bioavailability than the S-enantiomer.
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .
authors.forename: Amrita
authors.initials: A
authors.lastname: Saxena
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .|b Academy of Scientific and Innovative Research , New Delhi , India .
authors.forename: Guru R
authors.initials: GR
authors.lastname: Valicherla
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .
authors.forename: Pankaj
authors.initials: P
authors.lastname: Joshi
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .
authors.forename: Rohit
authors.initials: R
authors.lastname: Saxena
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .
authors.forename: Srikanth H
authors.initials: SH
authors.lastname: Cheruvu
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .
authors.forename: Shome S
authors.initials: SS
authors.lastname: Bhunia
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .
authors.forename: Girish K
authors.initials: GK
authors.lastname: Jain
authors.affiliation: c Department of Pharmacy , Integral University , Lucknow , Uttar Pradesh , India , and.
authors.forename: Hefazat H
authors.initials: HH
authors.lastname: Siddiqui
authors.affiliation: d Medicinal and Processing Chemistry Division, CSIR - Central Drug Research Institute , Lucknow , Uttar Pradesh , India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: a Pharmacokinetics and Metabolism Division, CSIR - Central Drug Research Institute , Lucknow , India .|b Academy of Scientific and Innovative Research , New Delhi , India .
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002243:Carbolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010539:Permeability; D011817:Rabbits; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: C000592767:2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide; D002243:Carbolines; D013449:Sulfonamides
keywords: Bioavailability; dose proportionality; enantiomers; permeability; pharmacokinetics