Modified bile acids as carriers for peptides and drugs

Kramer, Werner; Wess, G.; Enhsen, Alfons; Falk, Eugen; Hoffmann, Axel; Neckermann, Georg; Schubert, Gerrit Alexander; Urmann, Matthias

doi:10.1016/s0168-3659(96)01599-4

Cited by 43 publications

(42 citation statements)

References 26 publications

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“…Along their way from sinusoidal blood into canalicular bile, circulating oligopeptides are either degraded by soluble blood proteases or membrane-associated organ peptidases 48 or they are degraded at the canalicular hepatocyte membrane by aminopeptidases N and dipeptidyl-peptidase IV. 49 Therefore, to stabilize linear L-amino acid peptides against degradation, the integration of D-amino acids might be helpful 34,35,50 but an inherent loss of biological activity must be expected. In this study a (L-ala) 4 tetrapeptide was made resistant against peptidases.…”

Section: Discussionmentioning

confidence: 99%

Hepatobiliary transport of bile acid amino acid, bile acid peptide, and bile acid oligonucleotide conjugates in rats

et al. 1999

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Uptake of drugs by bile acid carriers could account for the selectivity of drug actions in the gut and liver. We have previously shown that conjugation of xenobiotics with bile acids facilitates their transfer to hepatocytes and ileal enterocytes. In this study L-alanine and 2 biooligomers, the tetrapeptide L-(ala) 4 and a 15 mer oligodeoxynucleotide (ODN) were coupled covalently via linker molecules to the 3-position of bile acids. The L-alanine-coupled bile acid conjugates were rapidly taken up by the liver and efficiently eliminated into bile. These compounds mimicked hepatic transport of bile acids. Also in case of the tetrapeptide (ala) 4 , bile acid conjugation significantly improved hepatic and intestinal cell uptake and rendered the peptide conjugate resistant to peptidases. Because uptake by isolated hepatocytes was not dependent on sodium ions and was blocked by ochratoxin A, we assume basolateral transport by an oatp-type bile acid carrier. In the case of the 15 mer ODN, normal and bile acid-conjugated oligodeoxynucleotide appeared intact in bile but without marked improvement of hepatocellular uptake and biliary elimination. We conclude that bile acids can deliver small peptides to gut and parenchymal liver cells via bile acid transport pathways, whereas in the case of oligonucleotides an attached bile acid was not sufficient to shuttle them successfully into hepatocytes. (HEPATOLOGY 1999;30:1257-1268

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Section: Discussionmentioning

confidence: 99%

Hepatobiliary transport of bile acid amino acid, bile acid peptide, and bile acid oligonucleotide conjugates in rats

et al. 1999

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“…As shown by Kramer et al (13), a 3␤-conjugated drug-bile salt is secreted faster into bile than its respective 3␣ derivative. In accordance with these data for dissolved bile salt conjugates, liposomes bearing DSPE-3␤-LCT interfere to a greater extent with CT transport than liposomes bearing DSPE-3␣-LCT.…”

Section: Influence Of Stereochemistrymentioning

confidence: 94%

“…By covalently coupling a drug to a bile salt, the bile salt-transporting systems have been already used for hepatic drug delivery. Bile salt-drug conjugates are readily taken up by the hepatocytes, but uptake is followed by a fast excretion of the drug conjugate into the bile (12,13).…”

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confidence: 99%

Synthesis of phospholipid-conjugated bile salts and interaction of bile salt-coated liposomes with cultured hepatocytes

Pütz

Schmider

Nitschke

et al. 2005

Journal of Lipid Research

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Hepatocyte pathology is central to many severe liver diseases. For optimal treatment and minimal adverse effects, drug concentrations in the target cell should be high while the systemic exposure to the drug should be as low as possible. For hepatocyte-specific drug delivery, hepatotropic liposomes represent an attractive strategy. Such hepatotropic liposomes need a signal on their surface targeting them selectively and specifically to hepatocytes. Hepatocyte-specific targeting of liposomes has been achieved by covalently linking the ligand of a hepatocyte-specific receptor to a lipid moiety. The most prominent targeted receptor is the hepatic asialoglycoprotein receptor, which has been targeted by various galactosyllipids (1, 2) or by asialofetuin, a glycoprotein (3). Glycyrrhizin (4) and a soybean-derived sterylglucoside mixture (5) have been used to target hepatocytes via receptors that have not yet been identified at the molecular level. To date, all of these receptors lead to the endocytosis of bound liposomes.After targeting the liposomes to endocytosing receptors, Abbreviations: BSL, bile salt-bearing

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“…Similar values were obtained to modified bile acids markedly increases hepatic uptake of drugs and improves the intestinal absorption of peptides and in cocultures of BEC and RL-MG-24 cells, indicating that functional tight junctions have formed between the different poorly absorbable drugs. [89][90][91][92][93] The molecules show affinity to the hepatic and ileal bile acid transporters as shown by photocell types. Moreover, BEC reestablish their apical microvillar surface and exhibit a distinct polarity.…”

Section: Drug Targeting To the Livermentioning

confidence: 99%

Second International Ringberg Conference: ?Cell Biology and Molecular Basis of Liver Transport?

Wehner

Kinne²,

Petzinger³

1996

Hepatology

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In the 7 years since the 1st Ringberg conference on ''He-observed system is a Cif-transporter, which means that it is patic Transport of Organic Substances'' was held at Ringberg-specific for purines and uridine. The transporter was cloned Castle near Tegernsee in Bavaria, Germany, the molecular very recently by expression cloning in Xenopus laevis oobasis of transport in the liver has been investigated with cytes. 2 The 2.9-kb complementary DNA of the Na / -dependent great success. Several carrier proteins could be cloned and purine nucleoside transporter SPNT encodes a protein of 659 the molecular properties of hepatic transport systems are amino acid residues and an estimated molecular mass of 72 now better understood, e.g., their function, architecture, kd. Hydropathy analysis reveals 14 putative membrane spanmembrane insertion, expression, and subcellular localization. ning segments. In addition, new insights into the cell biology of hepatocelluMdr transporters, synonym P-glycoproteins, were discovlar membrane transport were obtained, including transport ered as plasma membrane transport ATPases that are overregulation by signal-transduction cascades and the involve-expressed in multidrug-resistant tumor cells. Mdr2 is a phosment of transport systems in pH homeostasis and cell volume pholipid translocator, whereas mdr1 and mdr3 confer the regulation. These items were the topics of the 2nd Interna-transport of drugs into bile. S. Ruetz (Montréal, Quebec, Cantional Ringberg Conference on ''Cell Biology and Molecular ada) presented results regarding the detailed characterizaBasis of Liver Transport.'' tion of mdr2-mediated phosphatidylcholine (PC) translocation in the canalicular membrane. Yeast mutants of the sec BIOCHEMISTRY AND MOLECULAR BIOLOGY6-4 strain, which expressed the mdr2 protein in the mem- OF TRANSPORTbrane of yeast secretory vesicles, were generated. By use of the fluorescent PC label 7-nitrobenzoxa-1,3-diazol phosphatiThe recent discovery of canalicular primary active trans-dylcholine, he finds that the mdr2 protein translocates specifport systems that are involved in the vectorial transport of ically PC but not phosphatidylethanolamine or phosphatidylcholephilic compounds into bile has markedly stimulated the serine from the outer leaflet to the inner leaflet of the vesicles. understanding of bile formation. Previous to this era, the This translocation is affected by vanadate and verapamil, but adenosine triphosphatase (ATPase) activity of canalicular it is insensitive to vesicle acidification or membrane depolarmembranes was mainly attributed to a Ca 2/ Mg 2/ -ATPase, ization. 3 When the vesicles accumulate taurocholate, PC an ectoenzyme cloned in 1989 by Lin and Guidotti. 1 As re-translocation is stimulated. Fifty micromoles of the bile acid viewed by I. M. Arias (Boston, MA), these enzymes degrade can act as a potential lipid solubilizer, extracting 7-nitroextracellular (intraluminal) adenosine triphosphate (ATP) to benzoxa-1,3-diazol phosphatidylcholine molecules from the adenosine diphosp...

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Modified bile acids as carriers for peptides and drugs

Cited by 43 publications

References 26 publications

Hepatobiliary transport of bile acid amino acid, bile acid peptide, and bile acid oligonucleotide conjugates in rats

Hepatobiliary transport of bile acid amino acid, bile acid peptide, and bile acid oligonucleotide conjugates in rats

Synthesis of phospholipid-conjugated bile salts and interaction of bile salt-coated liposomes with cultured hepatocytes

Second International Ringberg Conference: ?Cell Biology and Molecular Basis of Liver Transport?

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