The influence of bile salts on the distribution of simvastatin in the octanol/buffer system

Drug Dev Ind Pharm. 2016;42(4):661-7. doi: 10.3109/03639045.2015.1067626. Epub 2015 Jul 23.

Abstract

Introduction: Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability.

Methods: LogD values of SVA and SVL with or without bile salts were measured by liquid-liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes.

Results: Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results.

Conclusions: Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients.

Keywords: Bile salts; distribution coefficient; drug transport; hydrophilicity; simvastatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / chemistry
  • Anticholesteremic Agents / metabolism
  • Bile Acids and Salts / chemistry*
  • Bile Acids and Salts / metabolism
  • Buffers
  • Octanols / chemistry*
  • Octanols / metabolism
  • Simvastatin / chemistry*
  • Simvastatin / metabolism
  • Solubility

Substances

  • Anticholesteremic Agents
  • Bile Acids and Salts
  • Buffers
  • Octanols
  • Simvastatin