title: The influence of bile salts on the distribution of simvastatin in the octanol/buffer system.
abstract: BACKGROUND
  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.
authors.affiliation: a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia .
authors.forename: Maja
authors.initials: M
authors.lastname: Đanić
authors.affiliation: a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia .
authors.forename: Nebojša
authors.initials: N
authors.lastname: Pavlović
authors.affiliation: a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia .
authors.forename: Bojan
authors.initials: B
authors.lastname: Stanimirov
authors.affiliation: a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia .
authors.forename: Saša
authors.initials: S
authors.lastname: Vukmirović
authors.affiliation: b Institute of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, University of Belgrade , Belgrade , Serbia , and.
authors.forename: Katarina
authors.initials: K
authors.lastname: Nikolić
authors.affiliation: b Institute of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy, University of Belgrade , Belgrade , Serbia , and.
authors.forename: Danica
authors.initials: D
authors.lastname: Agbaba
authors.affiliation: a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia .|c Curtin Health Innovation Research Institute, School of Pharmacy, Curtin University , Perth , WA , Australia.
authors.forename: Momir
authors.initials: M
authors.lastname: Mikov
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry / Q000378:metabolism; D001647:Bile Acids and Salts / Q000737:chemistry* / Q000378:metabolism; D002021:Buffers; D000442:Octanols / Q000737:chemistry* / Q000378:metabolism; D019821:Simvastatin / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D002021:Buffers; D000442:Octanols; D019821:Simvastatin
keywords: Bile salts; distribution coefficient; drug transport; hydrophilicity; simvastatin