1. Improved oral bioavailability of BCS class 2 compounds by self nano-emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol.
- Author
-
Elgart A, Cherniakov I, Aldouby Y, Domb AJ, and Hoffman A
- Subjects
- Adrenergic beta-Antagonists metabolism, Adrenergic beta-Antagonists pharmacokinetics, Amiodarone metabolism, Amiodarone pharmacokinetics, Animals, Biological Availability, Caco-2 Cells, Cytochrome P-450 CYP3A metabolism, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacokinetics, Humans, Intestinal Absorption, Male, Propanolamines metabolism, Propanolamines pharmacokinetics, Rats, Rats, Wistar, Adrenergic beta-Antagonists administration & dosage, Amiodarone administration & dosage, Drug Delivery Systems methods, Emulsions chemistry, Enzyme Inhibitors administration & dosage, Propanolamines administration & dosage
- Abstract
Purpose: 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.
- Published
- 2013
- Full Text
- View/download PDF