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Pharmaceutical Research

, Volume 30, Issue 12, pp 3029–3044 | Cite as

Improved Oral Bioavailability of BCS Class 2 Compounds by Self Nano-Emulsifying Drug Delivery Systems (SNEDDS): The Underlying Mechanisms for Amiodarone and Talinolol

  • Anna Elgart
  • Irina Cherniakov
  • Yanir Aldouby
  • Abraham J. Domb
  • Amnon HoffmanEmail author
Research Paper

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.

Key words

first pass metabolism intestinal absorption intestinal solubilization intra-enterocyte metabolism lipophilic drugs P-gp efflux self emulsifying drug delivery systems 

Abbreviations

AM

Amiodarone

AUC

Area under the plasma drug concentration vs. time curve

BCS

Biopharmaceutics Classification System

BDDCS

Biopharmaceutics Drug Disposition System Classification

Cltot

Total body clearance

Cmax

Maximal concentration of drug in plasma

CsA

Cyclosporine A

GFJ

Grapefruit Juice

GI

Gastrointestinal

LDH

Lactate Dehydrogenase

P-gp

P-glycoprotein

PK

Pharmacokinetics

SNEDDS

Self Nano-Emulsifying Drug Delivery System

TEER

Transepithelial Electrical Resistance

Tmax

Time to reach maximal concentration of drug in plasma

Vss

Volume of distribution at steady state

Notes

Acknowledgments and Disclosures

This study was in part supported by the Nofar Program of the Israel Ministry of Commerce and Trade.

A. Hoffman and A. J. Domb are affiliated with the David R. Bloom Center for Pharmacy.

This work is a part of a Ph. D. thesis of Anna Elgart.

The authors would like to thank Dr. Wahid Khan for his excellent technical assistance.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Anna Elgart
    • 1
  • Irina Cherniakov
    • 1
  • Yanir Aldouby
    • 1
  • Abraham J. Domb
    • 1
  • Amnon Hoffman
    • 1
    Email author
  1. 1.Institute for Drug Research, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

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