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Drug Metabolism and Bioanalysis Letters

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ISSN (Print): 2949-6810
ISSN (Online): 2949-6829

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Research Article

Comparison of Ussing Chamber and Caco-2 Model in Evaluation of Intestinal Absorption Mechanism of Compounds from Different BCS Classifications

Author(s): Dong Tian, Yingxin Yang, Huiying Zhang, Hongwen Du, Hongyu Zhou and Tao Wang*

Volume 16, Issue 2, 2023

Published on: 04 October, 2023

Page: [105 - 112] Pages: 8

DOI: 10.2174/2949681016666230913105920

Price: $65

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Abstract

Background: Oral bioavailability (F), which is evaluated by permeability and solubility, is one of the key parameters in drug discovery. Currently, Caco-2 and Ussing chamber are both used in the study of intestinal permeability of drugs at different stages of drug development. However, comparative research between the Ussing chamber and Caco-2 for predicting the intestinal availability data (Fa×Fg) in humans has not been reported.

Methods: In the present study, we evaluated the permeability of 22 drugs in rat intestines by Ussing chamber and compared them with the reported permeability data from Caco-2. In addition, the active transport of gabapentin was evaluated by Ussing Chamber.

Results: Intestine segments were selected by corresponding absorption site for Ussing chamber analysis. BCS Class I and II compounds were more absorbed in the duodenum and jejunum, and Class III and IV compounds were more absorbed in the ileum. Papp values in the Caco-2 model were moderately correlated with human Fa×Fg (R2=0.722), and the Papp of the rat in the Ussing chamber revealed a better correlation with human Fa×Fg (R2=0.952). In addition, we also used the Ussing chamber to identify the transporter of gabapentin, and the results showed that the active absorption of gabapentin was related to LAT1.

Conclusion: Ussing chamber combined with rat intestinal tissue would be a significant tool for predicting the intestinal absorption and metabolism of compounds with diverse physiochemical characteristics.

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Graphical Abstract

[1]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[2]
Calvo, P.C.; Campo, O.; Guerra, C.; Castaño, S.; Fonthal, F. Design of using chamber system based on electrical impedance spectroscopy (EIS) to measure epithelial tissue. Sens. Biosensing Res., 2020, 29, 100357.
[http://dx.doi.org/10.1016/j.sbsr.2020.100357]
[3]
Hellriegel, E.T.; Bjornsson, T.D.; Hauck, W.W. Interpatient variability in bioavailability is related to the extent of absorption: Implications for bioavailability and bioequivalence studies. Clin. Pharmacol. Ther., 1996, 60(6), 601-607.
[http://dx.doi.org/10.1016/S0009-9236(96)90208-8] [PMID: 8988062]
[4]
van de Waterbeemd, H.; Smith, D.A.; Beaumont, K.; Walker, D.K. Property-based design: Optimization of drug absorption and pharmacokinetics. J. Med. Chem., 2001, 44(9), 1313-1333.
[http://dx.doi.org/10.1021/jm000407e] [PMID: 11311053]
[5]
Amidon, G.L.; Lennernäs, H.; Shah, V.P.; Crison, J.R. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 1995, 12(3), 413-420.
[http://dx.doi.org/10.1023/A:1016212804288] [PMID: 7617530]
[6]
Dahan, A.; Miller, J.M.; Amidon, G.L. Prediction of solubility and permeability class membership: Provisional BCS classification of the world’s top oral drugs. AAPS J., 2009, 11(4), 740-746.
[http://dx.doi.org/10.1208/s12248-009-9144-x] [PMID: 19876745]
[7]
Kansy, M.; Senner, F.; Gubernator, K. Physicochemical high throughput screening: Parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem., 1998, 41(7), 1007-1010.
[http://dx.doi.org/10.1021/jm970530e] [PMID: 9544199]
[8]
Hidalgo, I.J. Assessing the absorption of new pharmaceuticals. Curr. Top. Med. Chem., 2001, 1(5), 385-401.
[http://dx.doi.org/10.2174/1568026013395010] [PMID: 11899104]
[9]
Delie, F.; Rubas, W. A human colonic cell line sharing similarities with enterocytes as a model to examine oral absorption: Advantages and limitations of the Caco-2 model. Crit. Rev. Ther. Drug Carrier Syst., 1997, 14(3), 66.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v14.i3.20] [PMID: 9282267]
[10]
Sun, D.; Lennernas, H.; Welage, L.S.; Barnett, J.L.; Landowski, C.P.; Foster, D.; Fleisher, D.; Lee, K.D.; Amidon, G.L. Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharm. Res., 2002, 19(10), 1400-1416.
[http://dx.doi.org/10.1023/A:1020483911355] [PMID: 12425456]
[11]
Oswald, S.; Gröer, C.; Drozdzik, M.; Siegmund, W. Mass spectrometry-based targeted proteomics as a tool to elucidate the expression and function of intestinal drug transporters. AAPS J., 2013, 15(4), 1128-1140.
[http://dx.doi.org/10.1208/s12248-013-9521-3] [PMID: 23982336]
[12]
Artursson, P.; Palm, K.; Luthman, K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv. Drug Deliv. Rev., 2001, 46(1-3), 27-43.
[http://dx.doi.org/10.1016/S0169-409X(00)00128-9] [PMID: 11259831]
[13]
Lennernäs, H.; Palm, K.; Fagerholm, U.; Artursson, P. Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo. Int. J. Pharm., 1996, 127(1), 103-107.
[http://dx.doi.org/10.1016/0378-5173(95)04204-0]
[14]
Jezyk, N.; Li, C.; Stewart, B.H.; Wu, X.; Bockbrader, H.N.; Fleisher, D. Transport of pregabalin in rat intestine and Caco-2 monolayers. Pharm. Res., 1999, 16(4), 519-526.
[http://dx.doi.org/10.1023/A:1018866928335] [PMID: 10227706]
[15]
Bajka, B.H.; Gillespie, C.M.; Steeb, C.B.; Read, L.C.; Howarth, G.S. Applicability of the Ussing chamber technique to permeability determinations in functionally distinct regions of the gastrointestinal tract in the rat. Scand. J. Gastroenterol., 2003, 38(7), 732-741.
[http://dx.doi.org/10.1080/00365520310003101] [PMID: 12889559]
[16]
Miyake, M.; Kondo, S.; Koga, T.; Yoda, N.; Nakazato, S.; Emoto, C.; Mukai, T.; Toguchi, H. Evaluation of intestinal metabolism and absorption using the Ussing chamber system equipped with intestinal tissue from rats and dogs. Eur. J. Pharm. Biopharm., 2018, 122, 49-53.
[http://dx.doi.org/10.1016/j.ejpb.2017.09.015] [PMID: 28974435]
[17]
Miyake, M.; Koga, T.; Kondo, S.; Yoda, N.; Emoto, C.; Mukai, T.; Toguchi, H. Prediction of drug intestinal absorption in human using the Ussing chamber system: A comparison of intestinal tissues from animals and humans. Eur. J. Pharm. Sci., 2017, 96, 373-380.
[http://dx.doi.org/10.1016/j.ejps.2016.10.006] [PMID: 27721045]
[18]
Michiba, K.; Maeda, K.; Kurimori, K.; Enomoto, T.; Shimomura, O.; Takeuchi, T.; Nishiyama, H.; Oda, T.; Kusuhara, H. Characterization of the human intestinal drug transport with Ussing chamber system incorporating freshly isolated human jejunum. Drug Metab. Dispos., 2021, 49(1), 84-93.
[http://dx.doi.org/10.1124/dmd.120.000138] [PMID: 33087448]
[19]
Kondo, S.; Miyake, M. Simultaneous prediction of intestinal absorption and metabolism using the mini-Ussing chamber system. J. Pharm. Sci., 2019, 108(1), 763-769.
[http://dx.doi.org/10.1016/j.xphs.2018.10.046] [PMID: 30389567]
[20]
Sjögren, E.; Eriksson, J.; Vedin, C.; Breitholtz, K.; Hilgendorf, C. Excised segments of rat small intestine in Ussing chamber studies: A comparison of native and stripped tissue viability and permeability to drugs. Int. J. Pharm., 2016, 505(1-2), 361-368.
[http://dx.doi.org/10.1016/j.ijpharm.2016.03.063] [PMID: 27073083]
[21]
Murakami, T. Absorption sites of orally administered drugs in the small intestine. Expert Opin. Drug Discov., 2017, 12(12), 1219-1232.
[http://dx.doi.org/10.1080/17460441.2017.1378176] [PMID: 28920464]
[22]
Dickens, D.; Webb, S.D.; Antonyuk, S.; Giannoudis, A.; Owen, A.; Rädisch, S.; Hasnain, S.S.; Pirmohamed, M. Transport of gabapentin by LAT1 (SLC7A5). Biochem. Pharmacol., 2013, 85(11), 1672-1683.
[http://dx.doi.org/10.1016/j.bcp.2013.03.022] [PMID: 23567998]
[23]
Nguyen, T.V.; Smith, D.E.; Fleisher, D. PEPT1 enhances the uptake of gabapentin via trans-stimulation of b0,+ exchange. Pharm. Res., 2007, 24(2), 353-360.
[http://dx.doi.org/10.1007/s11095-006-9155-6] [PMID: 17192834]
[24]
Chen, C.; Zhou, H.; Guan, C.; Zhang, H.; Li, Y.; Jiang, X.; Dong, Z.; Tao, Y.; Du, J.; Wang, S.; Zhang, T.; Du, N.; Guo, J.; Wu, Y.; Song, Z.; Luan, H.; Wang, Y.; Du, H.; Zhang, S.; Li, C.; Chang, H.; Wang, T. Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: A microdialysis study in rats. Pharmacol. Res. Perspect., 2020, 8(2), e00575.
[http://dx.doi.org/10.1002/prp2.575] [PMID: 32266794]
[25]
Ponce, Y.M.; Pérez, M.A.C.; Zaldivar, V.R.; Sanz, M.B.; Mota, D.S.; Torrens, F. Prediction of intestinal epithelial transport of drug in (Caco-2) cell culture from molecular structure using in silico approaches during early drug discovery. J. Elec. Mol. Des., 2005, 4, 124-150.
[26]
Furubayashi, T.; Inoue, D.; Nishiyama, N.; Tanaka, A.; Yutani, R.; Kimura, S.; Katsumi, H.; Yamamoto, A.; Sakane, T. Comparison of various cell lines and three-dimensional mucociliary tissue model systems to estimate drug permeability using an in vitro transport study to predict nasal drug absorption in rats. Pharmaceutics, 2020, 12(1), 79.
[http://dx.doi.org/10.3390/pharmaceutics12010079] [PMID: 31963555]
[27]
Shekhawat, P.; Bagul, M.; Edwankar, D.; Pokharkar, V. Enhanced dissolution/caco-2 permeability, pharmacokinetic and pharmacodynamic performance of re-dispersible eprosartan mesylate nanopowder. Eur. J. Pharm. Sci., 2019, 132, 72-85.
[http://dx.doi.org/10.1016/j.ejps.2019.02.021] [PMID: 30797937]
[28]
Sevin, E.; Dehouck, L.; Fabulas-da Costa, A.; Cecchelli, R.; Dehouck, M.P.; Lundquist, S.; Culot, M. Accelerated Caco-2 cell permeability model for drug discovery. J. Pharmacol. Toxicol. Methods, 2013, 68(3), 334-339.
[http://dx.doi.org/10.1016/j.vascn.2013.07.004] [PMID: 23916595]
[29]
Lee, J.B.; Zgair, A.; Taha, D.A.; Zang, X.; Kagan, L.; Kim, T.H.; Kim, M.G.; Yun, H.; Fischer, P.M.; Gershkovich, P. Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays. Eur. J. Pharm. Biopharm., 2017, 114, 38-42.
[http://dx.doi.org/10.1016/j.ejpb.2016.12.027] [PMID: 28088633]
[30]
Pham-The, H.; Garrigues, T.; Bermejo, M.; González-Álvarez, I.; Monteagudo, M.C.; Cabrera-Pérez, M.Á. Provisional classification and in silico study of biopharmaceutical system based on Caco-2 cell permeability and dose number. Mol. Pharm., 2013, 10(6), 2445-2461.
[http://dx.doi.org/10.1021/mp4000585] [PMID: 23675957]
[31]
Dahan, A.; Amidon, G.L. Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am. J. Physiol. Gastrointest. Liver Physiol., 2009, 297(2), G371-G377.
[http://dx.doi.org/10.1152/ajpgi.00102.2009] [PMID: 19541926]
[32]
Zheng, Y.; Chen, X.; Benet, L.Z. Reliability of in vitro and in vivo methods for predicting the effect of P-glycoprotein on the delivery of antidepressants to the brain. Clin. Pharmacokinet., 2016, 55(2), 143-167.
[http://dx.doi.org/10.1007/s40262-015-0310-2] [PMID: 26293617]
[33]
von Borstel Smith, M.; Crofoot, K.; Rodriguez-Proteau, R.; Filtz, T.M. Effects of phenytoin and carbamazepine on calcium transport in Caco-2 cells. Toxicol. In Vitro, 2007, 21(5), 855-862.
[http://dx.doi.org/10.1016/j.tiv.2007.02.008] [PMID: 17412555]
[34]
Thwaites, D.T.; Cavet, M.; Hirst, B.H.; Simmons, N.L. Angiotensin-converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco-2) cells. Br. J. Pharmacol., 1995, 114(5), 981-986.
[http://dx.doi.org/10.1111/j.1476-5381.1995.tb13301.x] [PMID: 7780654]
[35]
Faried, A.; Bolly, H.M.; Hermanto, Y.; Achmad, A.; Halim, D.; Tjahjono, F.P.; Arifin, M.Z. Prognostic significance of L-type amino acid transporter-1 (LAT-1) expression in human astrocytic gliomas. J. Pharmacol. Exp. Ther., 2021, 23, 100939.
[36]
Burley, S.K. Impact of structural biologists and the Protein Data Bank on small-molecule drug discovery and development. J. Biol. Chem., 2021, 296, 100559.
[http://dx.doi.org/10.1016/j.jbc.2021.100559] [PMID: 33744282]
[37]
Masoudi-Sobhanzadeh, Y.; Omidi, Y.; Amanlou, M.; Masoudi-Nejad, A. Drug databases and their contributions to drug repurposing. Genomics, 2020, 112(2), 1087-1095.
[http://dx.doi.org/10.1016/j.ygeno.2019.06.021] [PMID: 31226485]
[38]
Rozehnal, V.; Nakai, D.; Hoepner, U.; Fischer, T.; Kamiyama, E.; Takahashi, M.; Yasuda, S.; Mueller, J. Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs. Eur. J. Pharm. Sci., 2012, 46(5), 367-373.
[http://dx.doi.org/10.1016/j.ejps.2012.02.025] [PMID: 22418036]
[39]
Sjöberg, Å.; Lutz, M.; Tannergren, C.; Wingolf, C.; Borde, A.; Ungell, A.L. Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. Eur. J. Pharm. Sci., 2013, 48(1-2), 166-180.
[http://dx.doi.org/10.1016/j.ejps.2012.10.007] [PMID: 23103351]
[40]
Mummaneni, V.; Amidon, G.L.; Dressman, J.B. Gastric pH influences the appearance of double peaks in the plasma concentration-time profiles of cimetidine after oral administration in dogs. Pharm. Res., 1995, 12(5), 780-786.
[http://dx.doi.org/10.1023/A:1016284214708] [PMID: 7479568]
[41]
Westphal, K.; Weinbrenner, A.; Giessmann, T.; Stuhr, M.; Franke, G.; Zschiesche, M.; Oertel, R.; Terhaag, B.; Kroemer, H.K.; Siegmund, W. Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P-glycoprotein. Clin. Pharmacol. Ther., 2000, 68(1), 6-12.
[http://dx.doi.org/10.1067/mcp.2000.107579] [PMID: 10945310]
[42]
Masaoka, Y.; Tanaka, Y.; Kataoka, M.; Sakuma, S.; Yamashita, S. Site of drug absorption after oral administration: Assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract. Eur. J. Pharm. Sci., 2006, 29(3-4), 240-250.
[http://dx.doi.org/10.1016/j.ejps.2006.06.004] [PMID: 16876987]
[43]
Kharasch, E.D.; Hoffer, C.; Whittington, D. The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br. J. Clin. Pharmacol., 2004, 57(5), 600-610.
[http://dx.doi.org/10.1111/j.1365-2125.2003.02053.x] [PMID: 15089813]
[44]
Takahashi, M.; Washio, T.; Suzuki, N.; Igeta, K.; Yamashita, S. The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans. J. Pharm. Sci., 2009, 98(11), 4343-4353.
[http://dx.doi.org/10.1002/jps.21708] [PMID: 19230019]
[45]
Guan, C.; Yang, Y.; Tian, D.; Jiang, Z.; Zhang, H.; Li, Y.; Yan, J.; Zhang, C.; Chen, C.; Zhang, J.; Wang, J.; Wang, Y.; Du, H.; Zhou, H.; Wang, T. Evaluation of an ussing chamber system equipped with rat intestinal tissues to predict intestinal absorption and metabolism in humans. Eur. J. Drug Metab. Pharmacokinet., 2022, 47(5), 639-652.
[http://dx.doi.org/10.1007/s13318-022-00780-x] [PMID: 35733077]

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