Inhibitors of the Apical Sodium-Dependent Bile Acid Transporter (ASBT) as Promising Drugs

Савельева, Е. Е.; Tyutrina, E. S.; Nakanishi, Takeo; Tamai, Ikumi; Salmina, Alla

doi:10.1134/s1990750821010078

Cited by 2 publications

(2 citation statements)

References 61 publications

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“…86 One of the potential side effects of these ASBT inhibitors would be the induction of diarrhea due to the triggering of malabsorption of the BAs/ BSs. 73,76,80,85 Off Label Indications of BASs. As discussed earlier, being antihyperlipidemic drugs, the predominant role of the bile acid sequestrants (BASs) in the human body is to lower/reduce the LDL-C levels in hypercholesterolemic patients, but these BASs can also be utilized for a few other indications that are not listed as approved uses in the product monographs.…”

Section: Indications Advantages and Their Limitationsmentioning

confidence: 99%

“…In that regard, an alternative approach to luminal sequestration of bile acids is reported and found efficacious for the pharmacotherapy approach of direct inhibition of ileal apical sodium-dependent bile acid transporter (ASBT). − The ASBT, also called IBAT, ISBT, or ABAT (a 348 amino acid membrane glycoprotein with a glycosylated extracellular amino terminus and cytosolic carboxyl terminus, indicating an odd number of transmembrane domains), is expressed at tissue sites and is responsible for the uptake of the BAs/BSs across the enterocyte brush border membrane. − ASBT inhibitors are the nonsystemic molecules that act locally at the ASBT site and have been shown to be effective in reducing LDL cholesterol in many recent studies. − The ASBT inhibitor is approved for use in the treatment of chronic constipation, , and several powerful ASBT inhibitors are in preclinical and clinical development for the treatment of cholestatic liver disease/pruritus , and safe to use for patients with type 2 diabetes mellitus (T2DM) . One of the potential side effects of these ASBT inhibitors would be the induction of diarrhea due to the triggering of malabsorption of the BAs/BSs. ,,, …”

Section: Polymeric Bass In the Market: Mechanism Indications Advantag...mentioning

confidence: 99%

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Bile Acid Sequestrants for Hypercholesterolemia Treatment Using Sustainable Biopolymers: Recent Advances and Future Perspectives

et al. 2022

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Bile acids, the endogenous steroid nucleus containing signaling molecules, are responsible for the regulation of multiple metabolic processes, including lipoprotein and glucose metabolism to maintain homeostasis. Within our body, they are directly produced from their immediate precursors, cholesterol C (low-density lipoprotein C, LDL-C), through the enzymatic catabolic process mediated by 7-α-hydroxylase (CYP7A1). Bile acid sequestrants (BASs) or amphiphilic resins that are nonabsorbable to the human body (being complex high molecular weight polymers/electrolytes) are one of the classes of drugs used to treat hypercholesterolemia (a high plasma cholesterol level) or dyslipidemia (lipid abnormalities in the body); thus, they have been used clinically for more than 50 years with strong safety profiles as demonstrated by the Lipid Research Council–Cardiovascular Primary Prevention Trial (LRC–CPPT). They reduce plasma LDL-C and can slightly increase high-density lipoprotein C (HDL-C) levels, whereas many of the recent clinical studies have demonstrated that they can reduce glucose levels in patients with type 2 diabetes mellitus (T2DM). However, due to higher daily dosage requirements, lower efficacy in LDL-C reduction, and concomitant drug malabsorption, research to develop an “ideal” BAS from sustainable or natural sources with better LDL-C lowering efficacy and glucose regulations and lower side effects is being pursued. This Review discusses some recent developments and their corresponding efficacies as bile removal or LDL-C reduction of natural biopolymer (polysaccharide)-based compounds.

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Section: Indications Advantages and Their Limitationsmentioning

confidence: 99%

Section: Polymeric Bass In the Market: Mechanism Indications Advantag...mentioning

confidence: 99%

Bile Acid Sequestrants for Hypercholesterolemia Treatment Using Sustainable Biopolymers: Recent Advances and Future Perspectives

et al. 2022

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Improvement of Antialveolar echinococcosis efficacy of novel Albendazole-Bile acids Derivatives with Enhanced Oral Bioavailability

Qin

Zhang

et al. 2023

PLoS Negl Trop Dis

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Alveolar echinococcosis (AE) is a chronic and fatal infectious parasitic disease, which has not been well-researched. Current recommended therapies for AE by the World Health Organization include complete removal of the infected tissue followed by two years of albendazole (ABZ), administered orally, which is the only effective first-line anti-AE drug. Unfortunately, in most cases, complete resection of AE lesions is impossible, requiring ABZ administration for even longer periods. Only one-third of patients experienced complete remission or cure with such treatments, primarily due to ABZ’s low solubility and low bioavailability. To improve ABZ bioavailability, albendazole bile acid derivative (ABZ-BA) has been designed and synthesized. Its structure was identified by mass spectrometry and nuclear magnetic resonance. Its physicochemical properties were evaluated by wide-angle X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and polarizing microscopy; it was compared with ABZ to assess its solubilization mechanism at the molecular level. To avoid the effects of bile acid on the efficacy of albendazole, the inhibitory effect of ABZ-BA on protoscolex (PSCs)s was observed in vitro. The inhibitory effect of ABZ-BA on PSCs was evaluated by survival rate, ultrastructural changes, and the expression of key cytokines during PSC apoptosis. The results showed that ABZ-BA with 4-amino-1-butanol as a linker was successfully prepared. Physicochemical characterization demonstrated that the molecular arrangement of ABZ-BA presents a short-range disordered amorphous state, which changes the drug morphology compared with crystalline ABZ. The equilibrium solubility of ABZ-BA was 4-fold higher than ABZ in vitro. ABZ-BA relative bioavailability (Frel) in Sprague-Dawley (SD) rats was 26-fold higher than ABZ in vivo. The inhibitory effect of ABZ-BA on PSCs was identical to that of ABZ, indicating that adding bile acid did not affect the efficacy of anti-echinococcosis. In the pharmacodynamics study, it was found that the ABZ-BA group had 2.7-fold greater than that of Albenda after 1 month of oral administration. The relative bioavailability of ABZ-BA is significantly better than ABZ due to the transformation of the physical state from a crystalline state to an amorphous state. Furthermore, sodium-dependent bile acid transporter (ASBT) expressed in the apical small intestine has a synergistic effect through the effective transport of bile acids. Therefore, we concluded that the NC formulation could potentially be developed to improve anti-AE drug therapy.

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Inhibitors of the Apical Sodium-Dependent Bile Acid Transporter (ASBT) as Promising Drugs

Cited by 2 publications

References 61 publications

Bile Acid Sequestrants for Hypercholesterolemia Treatment Using Sustainable Biopolymers: Recent Advances and Future Perspectives

Bile Acid Sequestrants for Hypercholesterolemia Treatment Using Sustainable Biopolymers: Recent Advances and Future Perspectives

Improvement of Antialveolar echinococcosis efficacy of novel Albendazole-Bile acids Derivatives with Enhanced Oral Bioavailability

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