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Journal of Lipid Research, Vol 31, 1433-1443, Copyright © 1990 by Lipid Research, Inc.
A Roda, A Minutello, MA Angellotti and A Fini
Two independent methods have been developed and compared to determine the
lipophilicity of a representative series of naturally occurring bile acids
(BA) in relation to their structure. The BA included cholic acid (CA),
chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), deoxycholic acid
(DCA), hyodeoxycholic acid (HDCA), ursocholic acid (UCA), hyocholic acid
(HCA), as well as their glycine and taurine amidates. Lipophilicity was
determined using a 1-octanol/water shake- flask procedure and the
experiments were performed at different pH and ionic strengths and at
initial BA concentrations below their critical micellar concentrations
(CMC) and the water solubility of the protonated form. The experimental
data show that both the protonated (HA) and ionized (A-) forms of BA can
distribute in 1-octanol, and consequently a partition coefficient for HA
(logP' HA) and for A- (logP' A-) must be defined. An equation to predict a
weighted apparent distribution coefficient (D) value as a function of pH
and pKa has been developed and fits well with the experimental data.
Differences between logP for protonated and ionized species for
unconjugated BA were in the order of 1 log unit, which increased to 2 for
glycine-amidate BA. The partition coefficient of the A- form increased with
Na+ concentration and total ionic strength, suggesting an ion-pair
mechanism for its partition into 1-octanol. Lipophilicity was also assessed
using reverse phase chromatography (C-18-HPLC), and a capacity factor (K')
for ionized species was determined. Despite a broad correlation with the
logP data, some BA behaved differently. The logP values showed that the
order of lipophilicity was DCA greater than CDCA greater than UDCA greater
than HDCA greater than HCA greater than CA greater than UCA for both the
protonated and ionized unconjugated and glycine-amidate BA, while the K'
data showed an inversion for some BA, i.e., DCA greater than CDCA greater
than CA greater than HCA greater than UDCA greater than HDCA greater than
UCA. The logP data fitted well with other indirect measurements of BA
monomeric lipophilicity such as albumin binding or accessible total
hydrophobic surface area data calculated by energy minimization and
molecular computer graphics. Differences between unconjugated and amidated
BA are consistent with the presence of an amide bond and a lower pKa when
pH dependence was studied. Capacity factors, on the other hand, were
related to properties of BA micelles such as cholesterol-solubilizing
capacity and membrane disruption, reflecting the BA detergency.(ABSTRACT
TRUNCATED AT 400 WORDS)
ARTICLES
Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC
Istituto di Chimica Analitica, Universita di Messina, Italy.
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