Sodium glycodeoxycholate and sodium deoxycholate as epithelial permeation enhancers: in vitro and ex vivo intestinal and buccal bioassays

被引:25
作者
Brayden, David J. [1 ,2 ]
Stuettgen, Vivien [1 ,2 ]
机构
[1] UCD, Sch Vet Med, Dublin, Ireland
[2] Univ Coll Dublin, Conway Inst, Dublin 4, Ireland
基金
爱尔兰科学基金会;
关键词
bile salts; sodium glycodeoxycholate; oral peptide delivery; Caco-2; cells; TR1146; buccal peptide delivery;
D O I
10.1016/j.ejps.2021.105737
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Bile salts were first tested as epithelial permeation enhancers (PEs) for the intestine and buccal routes over 20 years ago. They are not as popular as other PEs due to their non-specific mechanism of action and perceived toxicity potential. We revisited two of them by comparing efficacy and toxicity of sodium glycodeoxycholate (SGC) and sodium deoxycholate (DC) for both routes using in vitro and ex vivo methods. Cytotoxicity assays in Caco-2 cells revealed that both agents altered cellular parameters at concentrations >2 mM over 60 min. Both agents reduced the transepithelial resistance (TEER) and doubled the Papp of [H-3]-octreotide across isolated rat colonic mucosae mounted in Ussing chambers at 10 mM concentrations. In some studies, 10 mM GDC also increased the Papp of the paracellular marker, FITC-dextran 4000 (FD4) and the fluorescent peptide, FITC-LKP, across colonic mucosae. Tissue histology was intact despite some mild perturbation at 10 mM. In the buccal epithelial cell line, TR146, changes in cell parameters were also seen at 1.5 mM over 60 min for both agents, with slightly more sensitivity seen for DC. In isolated porcine buccal epithelial mucosae, GDC was slightly more potent and efficacious than DC at increasing the Papp of [C-14]-mannitol. It also increased the Papp of [H-3]-octreotide and FITC-LKP by similar to 3-fold across porcine buccal tissue without causing damage. Overall, GDC and DC were efficacious in intestinal and buccal models. Both cause mild perturbation leading to an increase in paracellular fluxes for hydrophilic molecules including peptides. Their moderate efficacy, low potency, and low toxicity in these models are similar to that of more established PEs in clinical trials.
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页数:12
相关论文
共 57 条
[11]   Salcaprozate sodium (SNAC) enhances permeability of octreotide across isolated rat and human intestinal epithelial mucosae in Ussing chambers [J].
Fattah, Sarinj ;
Ismaiel, Mohamed ;
Murphy, Brenda ;
Rulikowska, Aleksandra ;
Frias, Jesus M. ;
Winter, Desmond C. ;
Brayden, David J. .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2020, 154
[12]   Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro [J].
Gleeson, John P. ;
Heade, Joanne ;
Ryan, Sinead M. ;
Brayden, David J. .
PEPTIDES, 2015, 71 :1-7
[13]   GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions [J].
Gutniak, MK ;
Larsson, H ;
Sanders, SW ;
Juneskans, O ;
Holst, JJ ;
Ahren, B .
DIABETES CARE, 1997, 20 (12) :1874-1879
[14]   Potential therapeutic level of glucagon-like peptide I achieved in humans by a buccal tablet [J].
Gutniak, MK ;
Larsson, H ;
Heiber, SJ ;
Juneskans, OT ;
Holst, JJ ;
Ahren, B .
DIABETES CARE, 1996, 19 (08) :843-848
[15]   The continuing importance of bile acids in liver and intestinal disease [J].
Hofmann, AF .
ARCHIVES OF INTERNAL MEDICINE, 1999, 159 (22) :2647-2658
[16]   In-vivo buccal delivery of fluorescein isothiocyanate dextran 4400 with glycodeoxycholate as an absorption enhancer in pigs [J].
Hoogstraate, AJ ;
Verhoef, JC ;
Tuk, B ;
Pijpers, A ;
vanLeengoed, LAMG ;
Verheijden, JHM ;
Junginger, HE ;
Bodde, HE .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1996, 85 (05) :457-460
[17]   Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers [J].
Hubatsch, Ina ;
Ragnarsson, Eva G. E. ;
Artursson, Per .
NATURE PROTOCOLS, 2007, 2 (09) :2111-2119
[18]   TR146 CELLS GROWN ON FILTERS AS A MODEL FOR HUMAN BUCCAL EPITHELIUM .1. MORPHOLOGY, GROWTH, BARRIER PROPERTIES, AND PERMEABILITY [J].
JACOBSEN, J ;
VANDEURS, B ;
PEDERSEN, M ;
RASSING, MR .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 1995, 125 (02) :165-184
[19]  
Kidron M., Patent No. [20070087957A1, 20070087957]
[20]  
Kolli CS, 2015, ADV DEL SCI TECHNOL, P125, DOI 10.1007/978-1-4899-7558-4_6