title: Pharmacokinetic evaluation of a novel benzopyridooxathiazepine derivative as a potential anticancer agent.
abstract: OBJECTIVE
  The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated.
  
  
  METHODS
  The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method.
  
  
  RESULTS
  Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC0-∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 μg/ml at 35 min and then decayed with a half-life of 108 min. The AUC0-∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid.
  
  
  CONCLUSIONS
  In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent.
authors.affiliation: UDSL, EA 4481, UFR Pharmacie, Université Lille Nord de France, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bourdon
authors.forename: Marie
authors.initials: M
authors.lastname: Lecoeur
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebègue
authors.forename: Bernard
authors.initials: B
authors.lastname: Gressier
authors.forename: Michel
authors.initials: M
authors.lastname: Luyckx
authors.forename: Pascal
authors.initials: P
authors.lastname: Odou
authors.forename: Thierry
authors.initials: T
authors.lastname: Dine
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Goossens
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kambia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D005260:Female; D017208:Rats, Wistar; D013841:Thiazepines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D013841:Thiazepines