title: Improved oral bioavailability of BCS class 2 compounds by self nano-emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol.
abstract: OBJECTIVE
  Superior bioavailability of BCS Class 2 compounds incorporated into SNEDDS was previously reported. This study aims to elucidate the underlying mechanisms accountable for this phenomenon.
  
  
  METHODS
  SNEDDS of amiodarone (AM) and talinolol were developed. Pharmacokinetic parameters were assessed in vivo. Effect on intestinal permeability, P-gp efflux and toxicity was evaluated in vitro (Caco-2) and ex vivo (Ussing). Solubilization was assessed in vitro (Dynamic Lipolysis Model). Effect on intraenterocyte metabolism was evaluated using CYP3A4 microsomes.
  
  
  RESULTS
  Oral administration of AM-SNEDDS and talinolol-SNEDDS resulted in higher and less variable AUC and Cmax. In vitro, higher talinolol-SNEDDS Papp indicated Pgp inhibition. Lipolysis of AM-SNEDDS resulted in higher AM concentration in the fraction available for absorption. Incubation of AM-SNEDDS with CYP3A4 indicated CYP inhibition. SNEDDS didn't alter mannitol Papp and TEER. SNEDDS effect was transient.
  
  
  CONCLUSIONS
  Multiple mechanisms are accountable for improved bioavailability and reduced variability of Class-2 compounds by SNEDDS: increased solubilization, reduced intraenterocyte metabolism and reduced P-gp efflux. SNEDDS effect is reversible and doesn't cause intestinal tissue or cell damage. These comprehensive findings can be used for intelligent selection of drugs for which oral bioavailability will improve upon incorporation into SNEDDS, based on recognition of the drug's absorption barriers and the ability of SNEDDS to overcome them.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O.Box 12065, Jerusalem, 91120, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Elgart
authors.forename: Irina
authors.initials: I
authors.lastname: Cherniakov
authors.forename: Yanir
authors.initials: Y
authors.lastname: Aldouby
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Domb
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D000638:Amiodarone / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000319:Adrenergic beta-Antagonists; D004655:Emulsions; D004791:Enzyme Inhibitors; D011412:Propanolamines; C011550:talinolol; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000638:Amiodarone