Apical Sodium Dependent Bile Acid Transporter (ASBT, SLC10A2):  A Potential Prodrug Target

Balakrishnan, Anand; Polli, James E.

doi:10.1021/mp060022d

Cited by 149 publications

(103 citation statements)

References 76 publications

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“…ASBT is an efficient uptake system for bile acids but has not been shown to transport drugs. However, it is an attractive target for delivery of prodrugs designed as bile acid derivatives (Balakrishnan and Polli, 2006). Determining regional expression levels of drug and prodrug transporters provides indications about the site of intestinal absorption of a drug.…”

Section: Intestinal Solute Carrier Expression In Humansmentioning

confidence: 99%

Regional Distribution of Solute Carrier mRNA Expression Along the Human Intestinal Tract

Meier

Eloranta

Darimont³

et al. 2007

Drug Metab Dispos

202

166

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ABSTRACT:Intestinal absorption of drugs, nutrients, and other compounds is mediated by uptake transporters expressed at the apical enterocyte membrane. These compounds are returned to the intestinal lumen or released into portal circulation by intestinal efflux transporters expressed at apical or basolateral membranes, respectively. One important transporter superfamily, multiple members of which are intestinally expressed, are the solute carriers (SLCs). SLC expression levels may determine the pharmacokinetics of drugs that are substrates of these transporters. In this study we characterize the distribution of 15 human SLC transporter mRNAs in histologically normal biopsies from five regions of the intestine of 10 patients. The mRNA expression levels of CNT1, CNT2, apical sodium-dependent bile acid transporter (ABST), serotonin transporter (SERT), PEPT1, and OCTN2 exhibit marked differences between different regions of the intestine: the first five are predominantly expressed in the small intestine, whereas OCTN2 exhibits strongest expression in the colon. Two transporter mRNAs studied (OCTN1, OATP2B1) are expressed at similar levels in all gut sections. In addition, ENT2 mRNA is present at low levels across the colon, but not in the small intestine. The other six SLC mRNAs studied are not expressed in the intestine. Quantitative knowledge of transporter expression levels in different regions of the human gastrointestinal tract could be useful for designing intestinal delivery strategies for orally administered drugs. Furthermore, changes in transporter expression that occur in pathological states, such as inflammatory bowel disease, can now be defined more precisely by comparison with the expression levels measured in healthy individuals.

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Section: Intestinal Solute Carrier Expression In Humansmentioning

confidence: 99%

Regional Distribution of Solute Carrier mRNA Expression Along the Human Intestinal Tract

Meier

Eloranta

Darimont³

et al. 2007

Drug Metab Dispos

202

166

View full text Add to dashboard Cite

show abstract

“…Clinically, the intimate link between ASBT and cholesterol may be exploited via blockage of bile acid reuptake, resulting in reduced cholesterol levels (5)(6)(7)(8)(9); this establishes the pharmaceutical relevance of ASBT in treatment of hypercholesterolemia (1, 10 -14). Moreover, ASBT constitutes an attractive target for prodrug strategies aimed at increasing oral bioavailability of poorly absorbed drugs (15)(16)(17). Despite important clinical applications, the molecular mechanisms underlying ASBT transport are poorly understood.…”

mentioning

confidence: 99%

Conserved Aspartic Acid Residues Lining the Extracellular Loop I of Sodium-coupled Bile Acid Transporter ASBT Interact with Na+ and 7α-OH Moieties on the Ligand Cholestane Skeleton

Hussainzada

Silva

Zhang³

et al. 2008

Journal of Biological Chemistry

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Functional contributions of residues Val-99 -Ser-126 lining extracellular loop (EL) 1 of the apical sodium-dependent bile acid transporter were determined via cysteine-scanning mutagenesis, thiol modification, and in silico interpretation. Despite membrane expression for all but three constructs (S112C, Y117C, S126C), most EL1 mutants (64%) were inactivated by cysteine mutation, suggesting a functional role during sodium/bile acid co-transport. A negative charge at conserved residues Asp-120 and Asp-122 is required for transport function, whereas neutralization of charge at Asp-124 yields a functionally active transporter. D124A exerts low affinity for common bile acids except deoxycholic acid, which uniquely lacks a 7␣-hydroxyl (OH) group. Overall, we conclude that (i) Asp-122 functions as a Na ؉ sensor, binding one of two co-transported Na ؉ ions, (ii) Asp-124 interacts with 7␣-OH groups of bile acids, and (iii) apolar EL1 residues map to hydrophobic ligand pharmacophore features. Based on these data, we propose a comprehensive mechanistic model involving dynamic salt bridge pairs and hydrogen bonding involving multiple residues to describe sodium-dependent bile acid transporter-mediated bile acid and cation translocation.

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“…However, such detailed measurements are often not made, and so, we developed an approach for scaling of a single jejunal solubility to estimate solubility in other regions of the GI tract. In human, 95% of released bile salts undergo enterohepatic circulation (18) with the majority of the re-absorption occurring in the ileum via the apical sodium dependent bile acid transporter (34). We performed simulations of the human luminal bile acid concentrations at steady state based upon known human fed-state bile flow and bile salt concentrations taken from Zwart (18).…”

Section: Prediction Of In Vivo Solubilitymentioning

confidence: 99%

Predicting Pharmacokinetics of Drugs Using Physiologically Based Modeling—Application to Food Effects

Parrott

Lukáčová

Fraczkiewicz

et al. 2009

AAPS J

134

120

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Abstract. Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in development have distinctly sub-optimal biopharmaceutical properties, making the quantitative prediction of food effect for different formulations from in vitro data very challenging. If such drugs reach clinical development and show undesirable variability when dosed with food, improved formulation can help to reduce the food effect and carefully designed in vivo studies in dogs can be a useful guide to clinical formulation development. Even so, such in vivo studies provide limited throughput for screening, and food effects seen in dog cannot always be directly translated to human. This paper describes how physiologically based absorption modeling can play a role in the prediction of food effect by integrating the data generated during pre-clinical and clinical research and development. Such data include physicochemical and in vitro drug properties, biorelevant solubility and dissolution, and in vivo pre-clinical and clinical pharmacokinetic data. Some background to current physiological absorption models of human and dog is given, and refinements to models of in vivo drug solubility and dissolution are described. These are illustrated with examples using GastroPlus™ to simulate the food effect in dog and human for different formulations of two marketed drugs.

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Apical Sodium Dependent Bile Acid Transporter (ASBT, SLC10A2): A Potential Prodrug Target

Cited by 149 publications

References 76 publications

Regional Distribution of Solute Carrier mRNA Expression Along the Human Intestinal Tract

Regional Distribution of Solute Carrier mRNA Expression Along the Human Intestinal Tract

Conserved Aspartic Acid Residues Lining the Extracellular Loop I of Sodium-coupled Bile Acid Transporter ASBT Interact with Na+ and 7α-OH Moieties on the Ligand Cholestane Skeleton

Predicting Pharmacokinetics of Drugs Using Physiologically Based Modeling—Application to Food Effects

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