Colesevelam (hydrochloride)

Colesevelam hydrochloride is an orally active bile acid sequestrant, lipid-lowering agent, and glycemic control agent. Colesevelam hydrochloride binds bile acids in the gastrointestinal tract to form nonabsorbable complexes, interrupts enterohepatic recirculation and increases fecal bile acid elimination. Colesevelam hydrochloride modulates FXR, TGR5, and Cyp7a1 activity and triggers cAMP signaling and GLP-1 release. Colesevelam hydrochloride alters hepatic lipid and glucose metabolism, suppresses hepatic glycogenolysis, reduces hepatic triglyceride and cholesterol levels, and increases LDL-C (low-density lipoprotein cholesterol) clearance. Colesevelam hydrochloride can be used for the research of type 2 diabetes mellitus, hypercholesterolemia, and alcohol-related liver disease^[1][2][3][4]. In Vitro: Colesevelam hydrochloride (5 mg/mL; 45 min incubation with taurocholic acid and oleic acid, followed by real-time cell treatment) forms a complex with taurocholic acid that activates human TGR5-mediated cAMP signaling in HEK293 TGR5-BRET cells, demonstrating that bile acids bound to Colesevelam hydrochloride retain TGR5 agonist activity^[1].
Colesevelam hydrochloride (1 h) maintains stable bile acid binding affinity and capacity after suspension in common beverages, exhibits greater total bile acid binding (including higher affinity for GC) than traditional bile acid sequestrants under physiological conditions, and is four to six times as potent as these traditional agents^[4]. In Vivo: Colesevelam hydrochloride (2%; oral; ad libitum; 7 days) suppresses hepatic glycogenolysis and reduces hyperglycemia in diet-induced obese mice via a TGR5/GLP-1-dependent mechanism, while improving cholesterol metabolism via an FXR-dependent, TGR5/GLP-1-independent mechanism^[1].
Colesevelam hydrochloride (rectal) complexed with taurocholic acid is sufficient to induce GLP-1 release in normal mice^[1].
Colesevelam hydrochloride (2%; oral; daily; from day 6 until study end) treatment mitigates ethanol-induced liver steatosis in humanized gnotobiotic mice by reducing hepatic lipid accumulation and related gene expression, but significantly increases serum liver injury markers and does not improve intestinal barrier function^[2].