Estimation of the increase in solubility of drugs as a function of bile salt concentration.
OBJECTIVE
The objective of this study was to develop a model to predict the extent to which bile salts can enhance the solubility of a drug, based on the physicochemical properties of the compound. The ability to predict bile salt solubilization of poorly soluble drugs would be a key component in determining which drugs will exhibit fed vs. fasted differences in drug absorption.


METHODS
A correlation between the logarithm of the octanol/water partition coefficient [log P] of six steroidal compounds and their solubilities in the presence of various concentrations of sodium taurocholate at 37 degrees C, log [SR] = 2.234 + 0.606 log [P] (r2 = 0.987) where SR is the ratio of the stabilization capacity of the bile salt to the solubilization capacity of water for the drug, was used to predict the solubility of the compounds in presence of sodium taurocholate were then measured.


RESULTS
The predicted solubilities were within 10% of the experimentally observed solubilities for griseofulvin, cyclosporin A and pentazocine. The model overpredicted the solubility of phenytoin and diazepam in 15 mM sodium taurocholate solution by a factor of 1.33 and 1.62 respectively.


CONCLUSIONS
The expected increase in solubility as a function of bile salt concentration can be estimated on the basis of the partition coefficient and aqueous solubility of the compound.
Mithani
S D
SD
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Bakatselou
V
V
TenHoor
C N
CN
Dressman
J B
JB
D001647:Bile Acids and Salts / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D016572:Cyclosporine / Q000493:pharmacokinetics; D003975:Diazepam / Q000493:pharmacokinetics; D005215:Fasting / Q000502:physiology*; D005502:Food; D006118:Griseofulvin / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000502:physiology*; D008956:Models, Chemical; D010423:Pentazocine / Q000493:pharmacokinetics; D010672:Phenytoin / Q000493:pharmacokinetics; D012995:Solubility; D013256:Steroids / Q000493:pharmacokinetics*; D013656:Taurocholic Acid / Q000494:pharmacology
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D013256:Steroids; D006118:Griseofulvin; D013656:Taurocholic Acid; D010672:Phenytoin; D016572:Cyclosporine; D003975:Diazepam; D010423:Pentazocine