Cholestyramine binds bile acids in the intestinal lumen, thereby inhibiting intestinal bile acid absorption. This results in decreased enterohepatic circulation of bile acids and increased hepatic bile acid synthesis from cholesterol. [2]

After 24 hours of treatment, cholestyramine (0.1–50 μg/mL) caused the most noticeable effects; efflux was 65% higher than in control cells. As an anion exchange resin, cholestyramine is water insoluble. ether, chloroform, and ethanol. Choleestyramine was first moistened with a tiny amount of DMSO and then diluted with medium for the experiment. Dimethyl sulfoxide (DMSO) was used to generate a blank sample devoid of cholestyramine, which did not differ from the control sample [3].

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In human microvascular endothelial HMEC-1 cells prelabeled with [3H]cholesterol, cholestyramine (at concentrations of 1, 5, 10, and 50 μg/ml) showed the largest efflux of cholesterol compared to other anticholesterol drugs. After 48 hours of exposure, it lowered cholesterol levels from 15% to 65% of control cell counts in a dose-dependent manner. At 1 μg/ml, reduction was 17%; at 5 μg/ml, 35%; at 50 μg/ml, 65% (24-hour incubation gave 58% reduction at 50 μg/ml). [3]
Cholestyramine is insoluble in water, alcohol, chloroform, and ether; for the assay it was initially wetted with a small amount of dimethyl sulfoxide before further dilution with media. A blank sample with dimethyl sulfoxide without cholestyramine displayed no differences from control samples. [3]

The bile acid-binding resin cholestyramine prevents the absorption of bile acid in the digestive tract, which can result in? boosts the production of cholesterol via bile acid [1]. According to the findings, cholestyramine alone had a different regulatory effect on the metabolism of TG, BA, and cholesterol than did GSPE therapy alone or in combination with it. Interestingly, cholestyramine markedly increased the expression of the sodium-dependent bile acid transporter (Asbt) gene at the intestinal apex, while GSPE considerably decreased it. as GSPE or cholestyramine were administered alone or in combination, they dramatically increased the expression of genes involved in hepatic BA biosynthesis, particularly cholesterol 7α-hydroxylase (Cyp7a1), as compared to the control. The induction of intestinal and hepatic cholesterol-generating gene expression was seen upon cholestyramine treatment; however, the induction of liver cholesterol-generating gene expression was not affected by coadministration of GSPE. Hepatic lipogenic gene expression is also induced by cholestyramine and can be reduced by co-administration with GSPE [2].

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In wild-type C57BL/6J mice, administration of cholestyramine (2% w/w mixed into food for 2 weeks) significantly increased reverse cholesterol transport (RCT) by 3.6-fold (p<0.001) primarily within fecal bile acids, but also within neutral sterols (p<0.001). Cholestyramine decreased intestinal cholesterol absorption by 24% (p<0.01) as determined by dual isotope method. Fecal bile acid excretion was increased several fold during all sampling periods (p<0.001), and fecal excretion of neutral sterols was also higher than in controls (0-4h and 24-48h p<0.001; 4-24h p<0.01). Cholestyramine treatment did not change baseline levels of plasma free or total cholesterol or triglycerides. However, upon rHDL administration, plasma free cholesterol levels decreased in cholestyramine-treated mice at 4h (p<0.001), and at later time points (24h p<0.01, 48h p<0.001) plasma free cholesterol levels were increased in response to rHDL. [1]
In C57BL/6 mice fed a 2% cholestyramine-supplemented diet for 4 weeks, cholestyramine significantly induced intestinal Asbt expression, and reduced Fgf15 expression (consistent with previous reports). Hepatic Cyp7a1 expression was induced 8-fold compared to control, and combined with GSPE further increased to nearly 13-fold. Cyp8b1 expression was increased by cholestyramine. Cholestyramine significantly increased hepatic expression of Hmgcs1, Hmgcr, Ldlr, and Srebp1c, as well as its target genes Fasn, Acc1, and Scd1. Serum bile acid levels were significantly reduced, serum cholesterol levels were reduced (p<0.05 for CHY vs CON), serum triglycerides were reduced (p<0.01 for CHY vs CON), and serum non-esterified fatty acids were reduced (p<0.001 for CHY vs CON). Fecal bile acid excretion was significantly increased (p<0.0001), fecal total lipids increased (p<0.0001), fecal cholesterol increased (p<0.01), and fecal non-esterified fatty acids increased (p<0.01) compared to control. [2]
In vivo, it has been reported that cholestyramine produces a 15-25% reduction in total serum cholesterol by combining with bile salts in the digestive system, preventing their reabsorption, and leading to fecal excretion. Gemfibrozil and cholestyramine have both been shown to stimulate synthesis of apolipoprotein A-I, the major protein constituent of HDL particles, and both drugs have been shown to reduce the incidence of coronary heart disease in clinical trials. [3]

HMEC-1 cells (human microvascular endothelial cell line) were trypsinized and seeded into 24-well plates at 50,000 cells per well. Cells were labeled with radioactive cholesterol by adding 0.835 μCi/well of tritiated cholesterol (specific activity 58 Ci/mmol, purity ~95%) and incubated for 96 hours in a 5% CO2 environment at 37°C. After 96 hours, the media with tritiated cholesterol were removed by aspiration, and fresh growth media were added. Following a 1-hour incubation, the wash media were removed, and fresh media with appropriate dilution of cholestyramine were added. Cholestyramine was initially wetted with a small amount of dimethyl sulfoxide before further dilution with media. All drug concentrations were shown to be below toxic levels. Following a 48-hour incubation, the test media were removed and plates were washed three times with Hank's buffered saline. Cells were harvested using a plate harvester, and samples were read on a liquid scintillation counter for cholesterol efflux. Radiolabeled cholesterol bound nonspecifically was less than 12.5% of control wells. [3]

In macrophage-to-feces reverse cholesterol transport studies, wild-type C57BL/6J mice received cholestyramine (2% w/w mixed into the food) for 2 weeks before animals were treated with either PBS vehicle or apoA-I-POPC (rHDL) as indicated. [1]
Eight-week old male C57BL/6 mice were fed either a control (standard chow) or a 2% cholestyramine-supplemented diet for 4 weeks (n=18 per group). After 4 weeks, mice in each group were randomly assigned to one of two treatment groups and orally gavaged with either vehicle (water) or grape seed procyanidin extract (GSPE, 250 mg/kg) and terminated 14 hours later (n=9 per experimental group). Blood was collected from the orbital plexus under isoflurane anesthesia, and intestines and livers were snap-frozen in liquid nitrogen and stored at -80°C. At the start of the 14-hour experiment, mice were placed into clean cages, and feces were manually collected at the end of the study, air-dried and weighed. [2]

Absorption, Distribution and Excretion
Previous studies on isolated gastric tissue and healthy volunteers have demonstrated that the ion-exchange resin cholestyramine possesses mucosal adhesion properties. This study aimed to clarify whether surface charge affects this property. Gamma scintillation was performed on fasting healthy subjects after oral administration of either cholestyramine or the cation-exchange resin Amberlite® IRP-69 (uncoated or polymer-coated to mask its charge). Subjects ate 4 hours later. Initial gastric emptying times were similar for all formulations (T₅₀ values (mean ± standard error): cholestyramine = 85.86 ± 9.16 min; IRP-69 = 76.09 ± 9.23 min; polymer-coated cholestyramine = 72.0 ± 12.64 min; polymer-coated IRP-69 = 70.25 ± 10.57 min; P = 0.724). However, after 3 hours, gastric emptying was slower for cholestyramine than for IRP-69. This results in a longer retention time than IRP-69 (AUC_0-6 values (relative units) = 15,200 ± 1093 vs. 9452 ± 811; cholestyramine vs. IRP-69; P = 0.0004). Polymer coating mitigates this effect. Serial images show that cholestyramine remains in the oropharynx and is subsequently displaced by food, resulting in a high level of activity even after 6 hours. Therefore, cholestyramine has a prolonged residence time in the stomach via mucosal adhesion and is distributed throughout the stomach. The surface charge of the resin was found to contribute to this. These materials may have the potential for drug delivery for local treatment of the gastric mucosa, such as for the eradication of Helicobacter pylori. It is not absorbed by the gastrointestinal tract.

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Interactions
Concomitant use of cholestyramine (cholinesterase diuretics, oral penicillin G, phenylbutazone, oral propranolol, oral tetracyclines) may cause these drugs to bind with cholestyramine, thereby reducing its absorption; it is recommended to take cholestyramine several hours apart from any of the above drugs. Cholestyramine may shorten the half-life of digitoxins (especially digoxin) by reducing intestinal reabsorption and enterohepatic circulation; caution is advised, especially when discontinuing cholestyramine if the patient's condition is stable while taking digitoxins, due to the risk of serious toxicity; some clinicians recommend taking cholestyramine approximately 8 hours after taking digitoxins. The efficacy of cholestyramine may be reduced when used concomitantly with chenodeoxycholic acid or ursodeoxycholic acid because cholestyramine binds to these drugs, reducing their absorption and potentially increasing cholesterol saturation in bile.
Concomitant use of cholestyramine may significantly enhance its anticoagulant effect due to vitamin K depletion; however, cholestyramine may also bind to oral anticoagulants in the gastrointestinal tract, reducing their efficacy. It is recommended to take an oral anticoagulant at least 6 hours before taking cholestyramine, and to adjust the anticoagulant dose based on frequent prothrombin time measurements.
For more complete data on cholestyramine resins (a total of 8 drug interactions), please visit the HSDB record page.

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In mice fed a 2% cholestyramine-supplemented diet for 4 weeks, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels remained within normal upper and lower limits, indicating no significant hepatotoxicity. [2]
In HMEC-1 cell assays, cholestyramine concentrations used (1-50 μg/ml) were shown to be below toxic levels and are close approximations of drug levels attained in vivo. [3]

[1]. rHDL administration increases reverse cholesterol transport in mice, but is not additive on top of ezetimibe or cholestyramine treatment. Atherosclerosis. 2013 Jul;229(1):94-101.

[2]. Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver. PLoS One. 2016; 11(4): e0154305.

[3]. Use of a human microvascular endothelial cell line as a model system to evaluate cholesterol uptake. Pathobiology. 1993;61(5-6):283-7.

strongly basic anion exchange resin whose main component is polystyrene trimethylbenzylammonium Cl(-) anion. See also: Cholestyramine (note moved to). Mechanism of Action: Cholestyramine binds to bile acids in the intestine, preventing their reabsorption and forming an insoluble complex that is excreted in feces. Therapeutic Uses: Ion exchange resin (bile salts); Anti-hyperlipoproteinemia. Cholestyramine is indicated for patients with primary hypercholesterolemia (type IIa hyperlipidemia) at significant risk of coronary artery disease, but for whom diet and other measures are ineffective. Cholestyramine lowers plasma total cholesterol and low-density lipoprotein (LDL) concentrations but does not cause changes or slight increases in serum triglyceride concentrations, therefore it is not suitable for patients with isolated triglyceride elevations. Its use in other types of hyperlipidemia (including type IIb hyperlipidemia) is limited due to the potential for further increases in triglycerides. /Included on US Product Label/
Colexamide is indicated for reducing the risk of atherosclerotic heart disease and myocardial infarction. /Included on US Product Label/
Colexamide is indicated for relieving itching caused by partial biliary obstruction, including primary biliary cirrhosis and various other forms of cholestasis. It is ineffective for patients with complete biliary obstruction or itching caused by other reasons. /Included on US Product Label/
For more complete data on the therapeutic uses of cholestyramine resins (8 in total), please visit the HSDB record page.

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Drug Warnings
The most common adverse reactions of cholestyramine involve the gastrointestinal tract, especially in high doses (more than 24 grams daily) and in patients over 60 years of age. The most common adverse reaction of cholestyramine resins is constipation, which occurs in approximately 20% of patients using the drug; cholestyramine resins may also worsen pre-existing constipation. Rarely, constipation can lead to fecal impaction and/or hemorrhoids (with or without bleeding), especially common in children and the elderly using high doses of cholestyramine. Other less common gastrointestinal adverse reactions of cholestyramine include abdominal pain and bloating, flatulence, nausea, vomiting, diarrhea, anorexia, dyspepsia, heartburn, biliary colic, and indigestion. Bloating and flatulence usually resolve with continued treatment. Other reported gastrointestinal adverse reactions include dysphagia, hiccups, ulceration, rectal bleeding, melena, acid reflux, pancreatitis, known duodenal ulcer bleeding, rectal pain, and diverticulitis; however, a direct relationship between these adverse reactions and drug treatment has not been established. The large amount of chloride released from cholestyramine resin may displace intestinal bicarbonate absorption, leading to hyperchloremic acidosis and increased urinary calcium excretion. This adverse reaction is more common in young patients or children taking high doses of the usual amount and can be partially offset by reducing chloride intake. Skin adverse reactions of cholestyramine include rash and irritation of the skin, tongue, and perianal area. For more complete data on drug warnings for cholestyramine resins (14 in total), please visit the HSDB records page.

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Cholestyramine is a bile acid binding resin that inhibits intestinal bile acid absorption leading to increased fecal bile acid excretion and in turn increased bile acid synthesis from cholesterol. This results in an increased flux through different compartments of cholesterol metabolism. Bile acid binding resins have been proven effective to reduce atherosclerosis in animal models as well as cardiovascular disease events in clinical outcome studies in patients. An unexpected finding was that cholestyramine did not only increase the fecal excretion of bile acids but also of cholesterol mass. Decreasing the availability of intestinal bile acids for micelle formation might represent the underlying mechanism for cholestyramine to increase fecal neutral sterol excretion. The overall stimulating effects of cholestyramine on reverse cholesterol transport were even significantly higher than the impact of ezetimibe on RCT. However, when co-administered with rHDL, cholestyramine did not impact the early mobilization of macrophage cholesterol to plasma. [1]
Cholestyramine may be prescribed to patients as a monotherapy or combination therapy with statins or other lipid-lowering agents to provide a more aggressive LDL-lowering regimen. Cholestyramine therapy may modestly increase triglyceride levels; dramatic increases usually occur in individuals with a metabolic defect affecting catabolism of triglyceride-containing lipoproteins, and it is not indicated for patients with pre-existing hypertriglyceridemia. [2]

C27H47N

385.66878

331.206

11041-12-6

137699107

White to off-white solid powder

1

2

8

30

329

0

POJQWPZVKOFVHS-UHFFFAOYSA-M

InChI=1S/C22H32N.C5H12.ClH.H3N/c1-6-20(16-18(2)21-10-8-7-9-11-21)22-14-12-19(13-15-22)17-23(3,4)5;1-4-5(2)3;;/h7-15,18,20H,6,16-17H2,1-5H3;5H,4H2,1-3H3;1H;1H3/q+1;;;/p-1

azane;2-methylbutane;trimethyl-[[4-(5-phenylhexan-3-yl)phenyl]methyl]azanium;chloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~1 mg/mL
H2O : ~0.1 mg/mL
1M HCl :< 1 mg/mL

Solubility in Formulation 1: 60 mg/mL (Infinity mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)