title: Pharmacokinetic and pharmacodynamics studies of nicotine after oral administration in mice: effects of methoxsalen, a CYP2A5/6 inhibitor.
abstract: BACKGROUND
  The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years.
  
  
  METHODS
  Studies were undertaken to examine whether the systemic administration of methoxsalen, an inhibitor of human CYP2A6 and mouse CYP2A5, would modulate nicotine pharmacokinetics and pharmacological effects (antinociception in the tail-flick, and hot-plate tests, and hypothermia) in male ICR mouse after acute oral nicotine administration.
  
  
  RESULTS
  Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine's Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment. Methoxsalen pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (15mg/kg, po) for periods up to 6- and 24-hr postnicotine administration, respectively. Additionally, methoxsalen potentiated nicotine-induced antinociception and hypothermia as evidenced by leftward shifts in nicotine's dose-response curve. Furthermore, this prolongation of nicotine's effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter pharmacological effects of nicotine given orally.
  
  
  CONCLUSIONS
  We have shown that the pharmacological effects of inhibiting nicotine's metabolism after oral administration in mice are profound. Our results suggest that inhibiting nicotine metabolism can be used to dramatically enhance nicotine's bioavailability and its resulting pharmacology, which further supports this inhibitory approach for clinical development of an oral nicotine replacement therapy.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Kingdom of Saudi Arabia;
authors.forename: Shakir D
authors.initials: SD
authors.lastname: Alsharari
authors.forename: Eric C K
authors.initials: EC
authors.lastname: Siu
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: Mohamad Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002853:Chromatography, Liquid; D003367:Cotinine / Q000097:blood / Q000493:pharmacokinetics; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004347:Drug Interactions; D007274:Injections, Intraperitoneal; D008297:Male; D008730:Methoxsalen / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009538:Nicotine / Q000097:blood* / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D003367:Cotinine; D008730:Methoxsalen