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PubMed1984

Differing effects of norcholate and cholate on bile flow and biliary lipid secretion in the rat.

The effects of norcholate (a C23 bile acid that differs from cholate in having a side chain containing four rather than five carbon atoms) on bile flow and biliary lipid secretion were compared with those of cholate, using the anesthetized rat with a bile fistula. Norcholate and cholate were infused intravenously over the range of 0.6-6.0 mumol X min-1 X kg-1. Both bile acids were quantitatively secreted into bile; norcholate was secreted predominantly in unconjugated form in contrast to cholate, which was secreted predominantly as its taurine or glycine conjugates. The increase in bile flow per unit increase in bile acid secretion induced by norcholate infusion [17 +/- 3.2 (SD) microliters/mumol, n = 8] was much greater than that induced by cholate infusion (8.6 +/- 0.9 microliters/mumol, n = 9) (P less than 0.001). Both bile acids induced phospholipid and cholesterol secretion. For an increase in bile acid secretion (above control values) of 1 mumol X min-1 X kg-1, the increases in phospholipid secretion [0.052 +/- 0.024 (SD) mumol X min-1 X kg-1, n = 9] and cholesterol secretion (0.0071 +/- 0.0033 mumol X min-1 X kg-1, n = 9) induced by norcholate infusion were much less than those induced by cholate infusion (0.197 +/- 0.05 mumol X min-1 X kg-1, n = 9, and 0.024 +/- 0.011 mumol X min-1 X kg-1, n = 9, respectively; P less than 0.001 for both phospholipid and cholesterol). The strikingly different effects of norcholate on bile flow and biliary lipid secretion were attributed mainly to its possessing a considerably higher critical micellar concentration than cholate.

Animals↗
PubMed1984

Aggregation patterns of bile salts: crystal structure of calcium cholate chloride heptahydrate.

Crystals of calcium cholate chloride heptahydrate, CaC24H39O7Cl . 7H2O, are monoclinic, space group P2(1), with a = 11.918(2), b = 8.636(1), c = 15.302(3) A, beta = 97.93(3) degrees, V = 1559.9(8) A3, and Z = 2. A trial structure was obtained by Patterson and Fourier techniques and was refined by full-matrix least-squares calculations using absorption corrected CuK-alpha diffractometer data. The final R index is 0.047. The crystal structure contains bilayer-type arrangements, with hydrophobic portions of cholate rings sandwiched between layers of polar groups that are interacting with calcium ions and water molecules. The calcium ion is coordinated to five water molecules and to the two carboxylate oxygen atoms of the cholate residue. Two additional water molecules are involved only in crystal packing through the formation of hydrogen bonds. Cholate-cholate hydrophobic interactions involve contacts between the hydrocarbon portions of the carboxylate sidechains and the A and B rings. This results in a staggered packing pattern that is nearly identical to that found in crystals of sodium cholate and rubidium deoxycholate. Similar bilayer aggregation patterns may also be involved in the formation of bile salt micelles in aqueous media. The characteristic bilayer packing arrangement can accommodate a variety of cation-binding patterns, as evidenced by the finding that calcium, sodium, and rubidium ions interact with the polar faces of the bilayers in different ways. The carboxylate sidechain displays two different conformations in the crystal structure of calcium cholate chloride heptahydrate. Variation in sidechain conformation may be of importance in the adjustment required to accommodate different cation coordination schemes.

Bile Acids and Salts↗
PubMed1999

Hyperlipidemia and atherosclerotic lesion development in LDL receptor-deficient mice fed defined semipurified diets with and without cholate.

Past studies of atherosclerosis in mice have used chow-based diets supplemented with cholesterol, lipid, and sodium cholate to overcome species resistance to lesion formation. Similar diets have been routinely used in studies with LDL receptor-deficient (LDLR(-/-)) mice. The nonphysiological nature and potential toxicity of cholate-containing diets have led to speculation that atherogenesis in these mice may not accurately reflect the human disease process. We have designed a semipurified AIN-76A-based diet that can be fed in powdered, pelleted, or liquid form and manipulated for the precise evaluation of diet-genetic interactions in murine atherosclerosis. LDLR(-/-) mice were randomly assigned among 4 diets (n=6/diet) as follows: 1, control, 10% kcal lipid; 2, high fat (40% kcal), moderate cholesterol (0.5% by weight); 3, high fat, high cholesterol (1.25% by weight); and 4, high fat, high cholesterol, and 0.5% (wt/wt) sodium cholate. Fasting serum cholesterol was increased in all cholesterol-supplemented mice compared with controls after 6 or 12 weeks of feeding (P<0.01). The total area of oil red O-stained atherosclerotic lesions was determined from digitally scanned photographs. In contrast to the control group, all mice in cholesterol-supplemented dietary groups 2 to 4 had lesions involving 7.01% to 12.79% area of the thoracic and abdominal aorta at 12 weeks (P<0.002, for each group versus control). The distribution pattern of atherosclerotic lesions was highly reproducible and comparable. The histological features of lesions in mice fed cholate-free or cholate-containing diets were similar. This study shows that sodium cholate is not necessary for the formation of atherosclerosis in LDLR(-/-) mice and that precisely defined semipurified diets are a valuable tool for the examination of diet-gene interactions.

Animal Feed↗
PubMedDate not supplied

Lead (II) cholate solubility.

In the framework of the research carried out on the behaviour of the salts of bile acids in aqueous solutions, the lead (II) cholate solubility was determined at 25 degrees C and in 0.100, 0.500 and 0.800 mol dm(-3) N(CH3)4Cl, as ionic medium. The change of its solubility was studied as a function of the cholate and hydrogen ion concentration. Solubility and electromotive force measurements of suitable galvanic cells were carried out and from the results lead (II) cholate solubility product could be calculated and the presence of associated species in solution in the ratio 1:3 and 1:4 between lead (II) and cholate was assumed. The relative constants were determined, as well. The results of this work allow us to obtain the free cholate concentration in equilibrium with solid lead (II) cholate.

Cholates↗
PubMed1995

Distinct systems mediate the unidirectional efflux of methotrexate and cholate in human CCRF-CEM cells.

Human CCRF-CEM cells were shown to contain energy-dependent and unidirectional efflux systems for the extrusion of methotrexate and cholate. Efflux activity was sensitive to temperature and to energy deprivation by treatment with antimycin A and to various other compounds which do not affect energy metabolism. A comparison of inhibitor sensitivities revealed that methotrexate and cholate efflux exhibit substantial differences in half-maximal inhibition (IC50) by indomethacin, reserpine, ethacrynic acid, ketoprofen, probenecid, and bromosulfophthalein, although these systems could not be distinguished by their responses to prostaglandin A1, meclofenamic acid, indoprofen, and biphenylacetic acid. Comparisons between cell lines showed that methotrexate efflux in CCRF-CEM cells exhibits an inhibitor response comparable to a secondary efflux system for methotrexate in L1210 cells (system II), whereas the inhibitor response of cholate efflux in CCRF-CEM cells resembles efflux system I in L1210 cells, the primary efflux route for both methotrexate and cholate. These results indicate that CCRF-CEM cells contain similar but separate systems for the efflux of methotrexate and cholate. CCRF-CEM cells thus differ from L1210 cells in that the latter mediate the efflux of methotrexate and cholate primarily via a single system.

Biological Transport↗
PubMed1999

Effect of Sublytic Concentrations of Sodium Cholate on Phospholipase C Hydrolysis of Phospholipid Bilayers.

Phospholipase C activity has been assayed with phosphatidylcholine as substrate in the presence of sodium cholate at concentrations well below those producing lipid solubilization. With short-chain phosphatidylcholine, which exists in monomeric form in aqueous solution, cholate has little or no effect. However, when the substrate is egg phosphatidylcholine in the form of bilayers, small cholate concentrations (below 1 mM, corresponding to an effective surfactant:lipid ratio below 0.05) increase the maximum enzyme rates by about threefold, while decreasing drastically the latency periods of enzyme activity. Previous studies from this laboratory have associated the phospholipase enhancing activity of a variety of amphiphiles to their ability to facilitate the formation of inverted hexagonal phospholipid structures, yet sodium cholate has the opposite effect, stabilizing the lamellar versus the inverted hexagonal phase. This suggests that cholate is activating phospholipase C through a hitherto undescribed mechanism. Sodium cholate concentrations above 1 mM decrease further the enzyme lag time, but they are less effective in enhancing enzyme rates. These observations may be pertinent in the analysis of biochemical data with purified lipases, as well as in physiological studies of biliary function. Copyright 1999 Academic Press.

Journal Article↗
PubMed1996

Hypercholeresis with cholate infusion in dogs with pigment gallstones.

We previously reported that dogs with pigment gallstones infused with taurocholate produce higher bile flow than normal dogs due to an increase in bile-acid independent bile flow. Since dogs with pigment gallstones are taurine-depleted and secrete large amounts of unconjugated bile salt, we hypothesized that the observed increased bile flow is secondary to the presence of unconjugated bile salts in the biliary tract, and cholate infusion was compared in normal and pigment gallstone dogs. Cholate increased bile flow significantly (P < 0.05) from 5.2 and 8.2 to 31 and 57 microliter/kg/min in normal and pigment gallstones dogs, respectively. Plots of bile flow versus bile acid output yielded separate linear relationships with a higher slope in gallstone dogs, but mannitol clearance indicated that excess flow originated in the canaliculus. Extended cholate infusion (570 min) severely taurine depleted normal dogs and increased cholate secretion, but bile flow remained significantly lower (P < 0.05) in normal dogs than in gallstone dogs. Choleretic activity of cholate in normal dogs was similar to that of taurocholate, but was nearly twice that of taurocholate in gallstone dogs. Choleretic activity increased in both groups with extended cholate infusion, suggesting adaptive changes in a biliary system bathed with unconjugated bile salts. These results are important since the increased bile flow in dogs with pigment gallstones would increase delivery of all biliary components to the gallbladder contributing to the high concentrations of gallbladder bile calcium previously observed in these dogs. It also has important physiological implications concerning the formation of bile in the proximal biliary tree. The data are most consistent with either direct hepatocyte stimulation to secrete another anion or with cholate/anion exchange at the canalicular, rather than ductal, level.

Animals↗
PubMed1984

Driving forces in hepatocellular uptake of phalloidin and cholate.

Active uptake of phalloidin and cholate in isolated rat liver cells depends upon both Na+ gradient and membrane potential. Omission of Na+ or inhibition of the (Na+ + K+)-ATPase diminished both phalloidin and cholate uptake. Dissipation of the sodium, potassium or proton gradient by monensin, nigericin, gramicidin and valinomycin blocked phalloidin uptake and also caused reduction of cholate transport. Chelation of Ca2+ and Mg2+ by EGTA or incubation of liver cells with NH4Cl neither influenced phalloidin nor cholate uptake. Hyperpolarization of liver cells by the lipophilic anions NO3- or SCN- enhanced phalloidin but reduced cholate uptake. Depolarization induced by a reversed K+ gradient reduced both kinds of transport. The results indicate that sodium ions and the membrane potential are driving forces for phalloidin and cholate uptake in hepatocytes.

Adenosine Triphosphate↗
PubMed1986

Cyclosporin A and a diaziridine derivative inhibit the hepatocellular uptake of cholate, phalloidin and rifampicin.

Cyclosporin A inhibits the uptake of cholate into isolated hepatocytes in a non-competitive manner (Ki = 3.6 microM). It protects liver cells against phalloidin injury by a mixed competitive/non-competitive inhibition of phalloidin uptake (Ki = 0.08 microM). Rifampicin, a well-known substrate of the bilirubin transporter is also incorporated in a decreased quantity in the presence of cyclosporin A (IC50 = 80 microM). A photolabile diaziridine derivative of cyclosporin A was used for the identification of binding sites. In comparison with the original cyclosporin A the photoaffinity label exhibits a 2-3-fold lower affinity to the cholate (and phalloidin) transporter in the liver cell membrane. In the dark the label inhibits the uptake of both cholate and of phalloidin reversibly; after treatment with ultraviolet light flashes the inhibition becomes irreversible. The degree of inhibition is concentration dependent. Our results suggest binding of cyclosporin A to protein components of the cholate (and phalloidin) transporter of liver cells without uptake by this system. The inhibition of cholate (and phalloidin) uptake by cyclosporin A is non-competitive and may be due to nonspecific hydrophobic binding to compounds of the cholate transporter.

Aminoisobutyric Acids↗
PubMed1986

Kinetic and structural aspects of reconstitution of phosphatidylcholine vesicles by dilution of phosphatidylcholine-sodium cholate mixed micelles.

Dilution of mixed micellar dispersions of egg phosphatidylcholine (PC) and sodium cholate beyond a critical value results in formation of cholate-containing PC vesicles. The structure of the resultant vesicles and some mechanistic aspects of this process have been investigated by the use of light scattering and nuclear magnetic resonance techniques. The main findings and conclusions are the following: Both the state of aggregation (micellar or vesicular) and the apparent equilibrium size distribution of micelles or vesicles obtained by dilution of the PC-cholate mixed micellar dispersions are a function of the cholate to PC molar ratio in the mixed aggregates (micelles or vesicles). When this effective ratio (Re) is higher than 0.4, the dispersion is micellar, and the size of the mixed micelles increases with decreasing Re; when Re less than 0.3, the dispersion is essentially vesicular, and the mean hydrodynamic radius of the vesicles is an increasing function of Re; in dispersions with 0.3 less than Re less than 0.4, mixed micelles and vesicles coexist. Addition of cholate to vesicular dispersions, to Re values below 0.3, results in vesicle size growth through a concentration-independent lipid-exchange mechanism. Addition of cholate to higher Re values results in micellization (solubilization) of the vesicles. On the other hand, dilution of vesicular dispersions does not affect the size of the vesicles. Apparent equilibration of a mixed micellar dispersion following dilution to Re values below 0.3 is slow (many hours). The overall process involves a series of three subsequent categories of steps: (i) a rapid (approximately 1-2 min) prevesiculation equilibration of micellar sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholic Acid↗
PubMed1997

Cholate inhibits high-fat diet-induced hyperglycemia and obesity with acyl-CoA synthetase mRNA decrease.

The effects of sodium cholate on high-fat diet-induced hyperglycemia and obesity were investigated. Insulin resistance was estimated by measuring 2-deoxyglucose uptake in epitrochlearis muscles incubated in vitro. Addition of 0.5% cholate to high-safflower oil diet completely prevented high fat-induced hyperglycemia and obesity in C57BL/6J mice with a slight decrease of energy intake but with no inhibition of fat absorption. Furthermore, the addition of cholate decreased blood insulin levels and prevented high-fat diet-induced decrease of glucose uptake in epitrochlearis. However, there was no change in the unsaturation index of fatty acids in skeletal muscles and in GLUT-4 levels by cholate. In liver, cholate addition resulted in cholesterol accumulation and completely prevented high-fat diet-induced triglyceride accumulation. The changes of triglyceride level in the liver were paralleled to the changes of acyl-CoA synthetase (ACS) mRNA. ACS catalyzes the formation of acyl-CoA from fatty acid, and acyl-CoA is utilized for triglyceride formation in liver. ACS has a sterol-responsive element 1 in its promoter region. These data indicate that the favorable effects of cholate could be partly the result of downregulation of ACS mRNA.

Analysis of Variance↗
PubMed1991

Cholate-independent retinyl ester hydrolysis. Stimulation by Apo-cellular retinol-binding protein.

Apo-cellular retinol-binding protein (apoCRBP) activated the hydrolysis of endogenous retinyl esters in rat liver microsomes by a cholate independent retinyl ester hydrolase. A Michaelis-Menten relationship was observed between the apoCRBP concentration and the rate of retinol formation, with half-maximum stimulation at 2.6 +/- 0.6 microM (mean +/- S.D., n = 5). Two other retinol-binding proteins, bovine serum albumin and beta-lactoglobulin, acceptors for the rapid and spontaneous hydration of retinol from membranes, had no effect up to 90 microM. These data suggest activation of the hydrolase by apoCRBP directly, rather than by facilitating removal of retinol from membranes. The hydrolase responding was the cholate-independent/cholate-inhibited retinyl ester hydrolase as shown by: 60% inhibition of the apoCRBP effect by 3 mM cholate; apoCRBP enhancement of retinyl ester hydrolysis in liver microsomes that had no detectable cholate-enhanced activity; inhibition of cholate-dependent, but not apoCRBP-stimulated retinyl ester hydrolysis by rabbit anti-rat cholesteryl esterase. Compared to the rate (mean +/- S.D. of [n] different preparations) supported by 5 microM apoCRBP in liver microsomes of 6.7 +/- 3.7 pmol/min/mg protein [10], microsomes from rat lung, kidney, and testes had endogenous retinyl ester hydrolysis rates of 1.8 +/- 0.3 [5], 0.5 +/- 0.2 [3], and 0.3 +/- 0.2 [5] pmol/min/mg protein, respectively. N-Ethylmaleimide and N-tosyl-L-phenylalanine chloromethyl ketone were potent inhibitors of apoCRBP-stimulated hydrolysis with IC50 values of 0.25 and 0.15 mM, respectively, but phenylmethylsulfonyl fluoride and diisopropyl-fluorophosphate were less effective with IC50 values of 1 mM, indicating the importance of imidazole and sulfhydryl groups to the activity. These data provide evidence of a physiological role for the cholate-independent hydrolase in retinoid metabolism and suggest that apoCRBP is a signal for retinyl ester mobilization.

Adrenal Glands↗
PubMed1994

Functional implications from the effects of 1-chloro-2,4-dinitrobenzene and ethacrynic acid on efflux routes for methotrexate and cholate in L1210 cells.

1-Chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid were examined for the ability to inhibit unidirectional efflux routes in L1210 cells that extrude both methotrexate and cholate (system I) and methotrexate alone (system II). These electrophiles were selected for study because of their known ability to undergo rapid intracellular conversion to glutathione conjugates. CDNB produced typical inhibitor kinetics and was a moderate inhibitor of both system I (IC50 = 4.8 microM) and system II (IC50 = 7.5 microM) with methotrexate as the substrate. However, a complex response was observed when cholate was employed as an alternative substrate for system I. Cholate efflux was stimulated initially at low levels of CDNB, but then slowed to a net inhibition as CDNB concentrations exceeded 10 microM. The latter characteristics for CDNB were not observed with ethacrynic acid, which produced a comparable inhibition of efflux system I regardless of the substrate employed (IC50 = 4.6 microM). Efflux measurements in an L1210/C7 variant which lacks system I confirmed that CDNB stimulates the activity of a substantial and unique efflux activity for cholate (system III). The inhibition of system I and II by CDNB and ethacrynic acid was not reversed by a wash step but required inhibitor removal and subsequent incubation at 37 degrees C. This slow reversal was attributed to a time-dependent clearance of inhibitory glutathione conjugates. A correlation between efflux systems for anions and anionic glutathione conjugates was demonstrated further by the ability of prostaglandin A1 and indomethacin, two potent inhibitors of methotrexate and cholate efflux, to inhibit the efflux of 2,4-dinitrophenyl-S-glutathione. These results support the hypothesis that efflux systems for methotrexate and cholate in L1210 cells are part of a family of efflux pumps which function in vivo to extrude various anions and anionic glutathione conjugates.

Adenosine Triphosphate↗
PubMedDate not supplied

Composition of sodium cholate micellar solutions.

To study the composition of sodium cholate solutions, an investigation was carried out at 25 degrees C and in N(CH3)4Cl, as a constant ionic medium, at three different concentrations (W = 0.100; 0.500 and 0.800 mol dm(-3)). Electromotive force measurements of three different galvanic cells, the first involving a glass electrode for hydrogen ions, the second an electrode for sodium ions and the third a lead amalgam electrode, were performed. Independently, lead (II) cholate solubility measurements in the presence of sodium ions were performed, as well. The experimental results obtained from both approaches were explained by assuming the formation of aggregates in cholate and sodium of different composition depending on W and on the cholate concentration. The maximum aggregation found number for cholate was 24 and even aggregation numbers were markedly predominant. Only two species with odd aggregation number were found, but at a low percentage. The assumed species and the relative constants were compared with those found for the other sodium salt of cholanic acids.

Cholic Acids↗
PubMed2005

Comparative regulation of major enzymes in the bile acid biosynthesis pathway by cholesterol, cholate and taurine in mice and rats.

These enzymes play important roles in the biosynthesis of bile acids. They are cholesterol 7alpha-hydroxylase (CYP7A1), the rate limiting enzyme in the classic pathway, sterol 12alpha-hydroxylase (CYP8B1), the key enzyme for synthesis of cholic acid (CA), and sterol 27-hydroxylase (CYP27), the initial enzyme in the alternative pathway. In the present study, the susceptibility of these three enzymes to dietary cholesterol and cholate, and the cholesterol lowering effect of taurine were determined in male C57BL/6 mice and Wistar rats. Both mice and rats were divided into 6 groups: control group (N), high cholesterol diet group (C), high cholesterol and cholate diet group (CB), and their 1% taurine-supplemented groups (NT, CT, CBT, respectively). After animals were fed with the respective diets for one week, the mRNA levels of CYP7A1 increased in the C-group compared with those of the N-group, and decreased in the CB-group compared with those of the C-group in both mice and rats. But the extent of decrease is different between the two species. CYP8B1 was also markedly repressed by cholate in mice, but not in rats. These results are consistent with the changes in serum and liver cholesterol concentrations. Taurine significantly increased CYP7A1 mRNA levels in the CBT-group compared with the CB-group in both animal models, with a subsequent decrease in serum and liver cholesterol levels and increase in fecal bile acid excretion. Up-regulated CYP8B1 was also observed after taurine supplementation in the CBT-group in mice. No increase in CYP7A1 was produced by taurine in the CT-group compared with that of the C-group in mice, although the changes of serum and liver cholesterol and fecal bile acids indicated taurine showed an efficient cholesterol lowering effect. In addition, CYP27 was induced in both C- and CB-groups of rats but not of mice, and no changes were produced by taurine. The overall results suggest that there are differences between mice and rats in susceptibility of the three enzymes to dietary cholesterol and cholate, and taurine induced CYP7A1 to produce its cholesterol-lowering effect only in the presence of cholate in the cholesterol diet.

Analysis of Variance↗
PubMed1998

Micelle formation of sodium cholate and solubilization into the micelle.

The micellization of sodium cholate (NaC) was studied at 298.2 K by aqueous solubility at different pH values. Using a stepwise association model of cholate anions without the sodium counterion, the aggregation number (n) of the cholate micelle was evaluated and found to increase with the total concentration, indicating that the mass action model worked quite well. The n value at 60 mM was found equal to 16. The membrane potential measurement of sodium ion with a cation exchange membrane was made in order to confirm the low counterion binding to micelle. The solubilization of alkylbenzenes (benzene, toluene, ethylbenzene, n-propylbenzene, n-butylbenzene, n-pentylbenzene, n-hexylbenzene) and polycyclic aromatic compounds (naphthalene, anthracene, pyrene) into the aqueous micellar solution of sodium cholate was carried out. Solubilizate concentrations at equilibrium were determined spectrophotometrically at 298.2 K. The first stepwise association constants (K1) between solubilizate monomer and vacant micelle were evaluated from the equilibrium concentrations and found to increase with increasing hydrophobicity of the solubilizate molecules. From the Gibbs energy change for solubilization at the different mean aggregation numbers and from molecular structure of the solubilizates, the function of sodium cholate micelle for solubilization was discussed and was compared with data from conventional aliphatic micelles.

Micelles↗
PubMed2003

Plastoquinones are effectively reduced by ferredoxin:NADP+ oxidoreductase in the presence of sodium cholate micelles. Significance for cyclic electron transport and chlororespiration.

The effect of sodium cholate and other detergents (Triton X-100, sodium dodecyl sulphate, octyl glucoside, myristyltrimethylammonium bromide) on the reduction of plastoquinones (PQ) with a different length of the side-chain by spinach ferredoxin:NADP(+) oxidoreductase (FNR) in the presence of NADPH has been studied. Both NADPH oxidation and oxygen uptake due to plastosemiquinone autoxidation were highly stimulated only in the presence of sodium cholate among the used detergents. Sodium cholate at the concentration of 20 mM was found to be the most effective on both PQ-4 and PQ-9-mediated oxygen uptake. The FNR-dependent reduction of plastoquinones incorporated into sodium cholate micelles was stimulated by spinach ferredoxin but inhibited by Mg(2+) ions. It was concluded that the structure of sodium cholate micelles facilitates contact of plastoquinone molecules with the enzyme and creates favourable conditions for the reaction similar to those found in thylakoid membranes for PQ-9 reduction. The obtained results were discussed in terms of the function of FNR as a ferredoxin:plastoquinone reductase both in cyclic electron transport and chlororespiration.

Anaerobiosis↗
PubMed2001

Development and validation of a cholate binding capacity method for DMP 504, a bile acid sequestrant.

DMP 504, a highly cross-linked insoluble polymer, is a bile acid sequestrant developed by the DuPont Pharmaceuticals Company for serum cholesterol reduction. Since DMP 504 is insoluble, it was necessary to develop unique specific analytical methods to measure and control the quality of different lots of the drug. Since the mechanism of action of DMP 504 is believed to be by sequestration of bile acids, the in-vitro binding capacity of the polymer for cholic acid was chosen as a surrogate of in-vivo performance and used to assess potency of the compound. In this method, individual aliquots of DMP 504 at three different levels were incubated with a cholate solution of known concentration. The residual cholate solution was filtered and analyzed by a reversed-phase HPLC method using refractive index detection. When the bound cholate was plotted versus the mass of DMP 504, the resulting curve was linear. The slope of this curve is the cholate binding capacity of DMP 504. This method has been shown to be precise and robust. Precision of the method was shown to have an RSD of 2.0% with injection precision of 0.4% and stability of cholate solutions up to 73 h. It is also a unique binding capacity method due to its multi-point determination, and it has been shown to be a suitable quality control method for ensuring lot-to-lot consistency of drug substance.

Cholates↗