Cholesterol (thermodynamic) activity determinations in bile salt-lecithin-cholesterol systems and cholesterol-rich liquid crystalline mesophase formation.
Previous in vitro studies have shown that tauroursodeoxycholate (TUDC)-lecithin (L) micellar solutions solubilize cholesterol (Ch) poorly compared to its 7 alpha-epimer, taurochenodeoxycholate (TCDC). However, in clinical studies ursodeoxycholic acid (UDC) has been found to be as effective as chenodeoxycholic acid (CDC) in Ch gallstone dissolution, and it has been suggested that, during UDC therapy, liquid crystalline mesophase formation may be involved in enhancing micellar Ch dissolution and dispersion. The purpose of the present study was to investigate whether measurements of the Ch thermodynamic activity (A(T) would provide new insights into the problem of Ch solubilization and mesophase formation in bile salt-lecithin-Ch systems. Using the silicone polymer uptake method developed in this laboratory, A(T) was measured as a function of Ch concentration in the TUDC-L-Ch and TCDC-L-Ch model bile systems. In the TCDC systems Henry's law was obeyed almost up to unit activity (i.e., A(T) was proportional to Ch concentration almost up to A(T) = 1.0). However, in many of the TUDC-containing systems negative deviations from Henry's law were observed well below unit activity and these systems became visibly turbid before saturation with respect to cholesterol monohydrate (ChM) was reached. The effects of varying the TCDC/TUDC ratio upon the A(T) behavior were also studied. With increasing TCDC/TUDC ratio, the onset of mesophase formation was shifted to higher A(T) values. A(T) measurements were also conducted in BS-L-Ch mixtures simulating biles of patients undergoing UDC therapy. The results obtained suggest that mesophase formation may not always occur in biles of patients undergoing UDC therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Jain
U K
UK
Department of Pharmaceutics, College of Pharmacy, University of Utah, Salt Lake City 84112.
Higuchi
W I
WI
Liu
C L
CL
Lee
P H
PH
Mazer
N A
NA
D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000737:chemistry*; D002138:Calibration; D002769:Cholelithiasis / Q000188:drug therapy; D002784:Cholesterol / Q000737:chemistry*; D003460:Crystallization; D008956:Models, Chemical; D010713:Phosphatidylcholines; D012995:Solubility; D012996:Solutions; D013816:Thermodynamics; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use
D001647:Bile Acids and Salts; D010713:Phosphatidylcholines; D012996:Solutions; D014580:Ursodeoxycholic Acid; D002784:Cholesterol