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.

A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

“…Therefore, based on the obtained results, the benzhydryl amidoxime could be a promising compound to treat all those pathological conditions in which nNOS activity is dysregulated. [b] value < 1.5 × 10 À 6 cm/s, low-permeability compounds; value > 1.5 × 10 À 6 cm/s, high-permeability compounds [46] ;…”

Metabolic profiling of a novel antithrombotic compound, S002‐333 and enantiomers: metabolic stability, species comparison and in vitro–in vivo extrapolation

“…The plasma concentration vs. time data obtained after a single i.v. bolus dose to male rabbits was subjected to non‐compartmental analysis with WinNonlin (version 5.1, Pharsight Corporation, Mountain View, USA) for S002‐333 and enantiomers, respectively . The observed whole body clearance ( CL ) was converted to the observed hepatic clearance CL H(obs) through the well‐stirred liver model with rabbit plasma protein binding corrections for S002‐333 and enantiomers.…”

Preparation, Characterization, and In Vivo Evaluation of an Oral Multiple Nanoemulsive System for Co-Delivery of Pemetrexed and Quercetin

“…The in vitro intestinal membrane permeability of PMX and PMX/DCK in water, PMX/DCK-loaded w/o/w NE (PMX/DCK-NE), QCN dispersed in water and in 0.3% NaCMC, and QCN-loaded w/o/w NE (QCN-NE) were evaluated by parallel artificial membrane permeability assay (BD Biosciences, San Jose, CA, USA) as described previously [ 36 ]. Briefly, PMX and QCN samples were diluted with PBS (pH 6.8) to final concentrations of 200 µg/mL and 400 µg/mL, respectively.…”