Relationship between structure and intestinal absorption of bile acids with a steroid or side-chain modification

Aldini, Rita; Roda, Aldo; Montagnani, Marco; Cerrè, Carolina; Pellicciari, Roberto; Roda, Enrico

doi:10.1016/s0039-128x(96)00119-5

Cited by 40 publications

(38 citation statements)

References 29 publications

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“…Studies using photoactivated bile acid derivatives specifi cally labeled an ‫ف‬ 87 kDa brush border membrane protein that was present along the entire length of rabbit small intestine ( 159 ). Elegant in vivo uptake and cis -inhibition studies using perfused jejunum demonstrated bile acid transport specifi city consistent with a facilitative carrier ( 160,161 ). In vitro studies using rat jejunal brush border membrane vesicles extended those fi ndings and clearly demonstrated conjugated bile acid uptake operating through an anion exchange mechanism ( 162 ).…”

Section: Bsepmentioning

confidence: 52%

Bile acid transporters

Dawson

Lan

Rao

2009

Journal of Lipid Research

592

456

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Section: Bsepmentioning

confidence: 52%

Bile acid transporters

Dawson

Lan

Rao

2009

Journal of Lipid Research

592

456

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“…Previously, we studied a large number of natural (Roda et al, 1987(Roda et al, , 1988Aldini et al, 1996) and semisynthetic BA analogs (Pellicciari et al, 2004(Pellicciari et al, , 2009 to elucidate the relationship between BA structure, physicochemical properties, pharmacokinetics, and metabolism. We defined the "critical" structurerelated values of their properties, which could predict their pharmacokinetics, metabolism, and biodistribution.…”

Section: Introductionmentioning

confidence: 99%

Semisynthetic Bile Acid FXR and TGR5 Agonists: Physicochemical Properties, Pharmacokinetics, and Metabolism in the Rat

Roda

Pellicciari

Gioiello

et al. 2014

J Pharmacol Exp Ther

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We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6a-ethyl-3a,7a-dihydroxy-5b-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6a-ethyl-23(S)-methyl-3a,7a,12a-trihydroxy-5b-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6a-ethyl-3a,7a-dihydroxy-24-nor-5b-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7a-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6a-ethyl-3a,7a-dihydroxy-5b-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6a-Ethyl-23(S)-methyl-3a,7a,12a-trihydroxy-5b-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6a-ethyl-3a,7a-dihydroxy-24-nor-5b-cholan-23-sulfate was secreted in bile unmodified and as 3-glucuronide. Therefore, minor structural modifications profoundly influence the metabolism and biodistribution in the target organs where these analogs exert therapeutic effects by interacting with FXR and/or TGR5 receptors.

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“…9 Unconjugated bile acids can enter cells by a sodium-independent transporter as well as by passive diffusion, which is a function of their respective hydrophobicity. [10][11][12][13] Through this latter mechanism, certain bile acids can traverse the cellular plasma membrane of tissues both inside and outside of the enterohepatic circulation. We previously reported that, in contrast to its taurine conjugate, the relatively hydrophilic ursodeoxycholic acid was taken up by cultured human fibroblasts in a dose-and time-dependent fashion and with a rate constant of approximately 4.6 ϫ 10 Ϫ4 nmol/mg protein/sec/µmol/L.…”

mentioning

confidence: 99%

Extrahepatic deposition and cytotoxicity of lithocholic acid: Studies in two hamster models of hepatic failure and in cultured human fibroblasts

et al. 1998

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Effects of bile acids on tissues outside of the enterohepatic circulation may be of major pathophysiological significance under conditions of elevated serum bile acid concentrations, such as in hepatobiliary disease. Two hamster models of hepatic failure, namely functional hepatectomy (HepX), and 2-day bile duct ligation (BDL), as well as cultured human fibroblasts, were used to study the comparative tissue uptake, distribution, and cytotoxicity of lithocholic acid (LCA) in relation to various experimental conditions, such as binding of LCA to low-density lipoprotein (LDL) or albumin as protein carriers. Fifteen minutes after iv infusion of [24-14 C]LCA, the majority of LCA in shamoperated control animals was recovered in liver, bile, and small intestine. After hepatectomy, a significant increase in LCA was found in blood, muscle, heart, brain, adrenals, and thymus. In bile duct-ligated animals, significantly more LCA was associated with blood and skin, and a greater than twofold increase in LCA was observed in the colon. In the hepatectomized model, the administration of LCA bound to LDL resulted in a significantly higher uptake in the kidneys and skin.

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Relationship between structure and intestinal absorption of bile acids with a steroid or side-chain modification

Cited by 40 publications

References 29 publications

Bile acid transporters

Bile acid transporters

Semisynthetic Bile Acid FXR and TGR5 Agonists: Physicochemical Properties, Pharmacokinetics, and Metabolism in the Rat

Extrahepatic deposition and cytotoxicity of lithocholic acid: Studies in two hamster models of hepatic failure and in cultured human fibroblasts

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