Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin

Objectives The Biopharmaceutics Classification System (BCS) categorizes active pharmaceutical ingredients according to their solubility and permeability properties, which are susceptible to matrix or formulation effects. The aim of this research was to evaluate the matrix effects of a hydroethanolic...

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Autores:
Domınguez More, Gina Paola
Tipo de recurso:
Fecha de publicación:
2019
Institución:
Universidad del Atlántico
Repositorio:
Repositorio Uniatlantico
Idioma:
eng
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oai:repositorio.uniatlantico.edu.co:20.500.12834/974
Acceso en línea:
https://hdl.handle.net/20.500.12834/974
Palabra clave:
Biopharmaceutics Classification System; Caco-2 cells; permeability; Physalis peruviana; rutin; solubility
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openAccess
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http://creativecommons.org/licenses/by-nc/4.0/
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dc.title.spa.fl_str_mv Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
title Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
spellingShingle Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
Biopharmaceutics Classification System; Caco-2 cells; permeability; Physalis peruviana; rutin; solubility
title_short Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
title_full Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
title_fullStr Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
title_full_unstemmed Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
title_sort Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin
dc.creator.fl_str_mv Domınguez More, Gina Paola
dc.contributor.author.none.fl_str_mv Domınguez More, Gina Paola
dc.contributor.other.none.fl_str_mv Feltrin, Clarissa
Freire Brambila, Paula
Cardona, Maria Isabel
Echeverry, Sandra Milena
Oliveira Simoes, Claudia Maria
Aragon, Diana Marcela
dc.subject.keywords.spa.fl_str_mv Biopharmaceutics Classification System; Caco-2 cells; permeability; Physalis peruviana; rutin; solubility
topic Biopharmaceutics Classification System; Caco-2 cells; permeability; Physalis peruviana; rutin; solubility
description Objectives The Biopharmaceutics Classification System (BCS) categorizes active pharmaceutical ingredients according to their solubility and permeability properties, which are susceptible to matrix or formulation effects. The aim of this research was to evaluate the matrix effects of a hydroethanolic extract of calyces from Physalis peruviana L. (HEE) and its butanol fraction (BF), on the biopharmaceutics classification of their major compound, quercetin-3-O-rutinoside (rutin, RU). Methods Rutin was quantified by HPLC-UV, and Caco-2 cell monolayer transport studies were performed to obtain the apparent permeability values (Papp). Aqueous solubility was determined at pH 6.8 and 7.4. Key findings The Papp values followed this order: BF > HEE > RU (1.77 0.02 > 1.53 0.07 > 0.90 0.03 9 10 5 cm/s). The lowest solubility values followed this order: HEE > RU > BF (2.988 0.07 > 0.205 0.002 > 0.189 0.005 mg/ml). Conclusions According to these results, rutin could be classified as BCS classes III (high solubility/low permeability) and IV (low solubility/low permeability), depending on the plant matrix. Further work needs to be done in order to establish how apply the BCS for research and development of new botanical drugs or for bioequivalence purposes.
publishDate 2019
dc.date.submitted.none.fl_str_mv 2019-08-07
dc.date.issued.none.fl_str_mv 2020-02-09
dc.date.accessioned.none.fl_str_mv 2022-11-15T21:19:10Z
dc.date.available.none.fl_str_mv 2022-11-15T21:19:10Z
dc.type.coarversion.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
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dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/article
dc.type.hasVersion.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.spa.spa.fl_str_mv Artículo
status_str publishedVersion
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/20.500.12834/974
dc.identifier.doi.none.fl_str_mv 10.1111/jphp.13248
dc.identifier.instname.spa.fl_str_mv Universidad del Atlántico
dc.identifier.reponame.spa.fl_str_mv Repositorio Universidad del Atlántico
url https://hdl.handle.net/20.500.12834/974
identifier_str_mv 10.1111/jphp.13248
Universidad del Atlántico
Repositorio Universidad del Atlántico
dc.language.iso.spa.fl_str_mv eng
language eng
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dc.rights.cc.*.fl_str_mv Attribution-NonCommercial 4.0 International
dc.rights.accessRights.spa.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0/
Attribution-NonCommercial 4.0 International
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eu_rights_str_mv openAccess
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.place.spa.fl_str_mv Barranquilla
dc.publisher.discipline.spa.fl_str_mv Farmacia
dc.publisher.sede.spa.fl_str_mv Sede Norte
dc.source.spa.fl_str_mv Blackwell Publishing Ltd
institution Universidad del Atlántico
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spelling Domınguez More, Gina Paolaab74cd74-91a6-459d-b23f-2af0d46b908aFeltrin, ClarissaFreire Brambila, PaulaCardona, Maria IsabelEcheverry, Sandra MilenaOliveira Simoes, Claudia MariaAragon, Diana Marcela2022-11-15T21:19:10Z2022-11-15T21:19:10Z2020-02-092019-08-07https://hdl.handle.net/20.500.12834/97410.1111/jphp.13248Universidad del AtlánticoRepositorio Universidad del AtlánticoObjectives The Biopharmaceutics Classification System (BCS) categorizes active pharmaceutical ingredients according to their solubility and permeability properties, which are susceptible to matrix or formulation effects. The aim of this research was to evaluate the matrix effects of a hydroethanolic extract of calyces from Physalis peruviana L. (HEE) and its butanol fraction (BF), on the biopharmaceutics classification of their major compound, quercetin-3-O-rutinoside (rutin, RU). Methods Rutin was quantified by HPLC-UV, and Caco-2 cell monolayer transport studies were performed to obtain the apparent permeability values (Papp). Aqueous solubility was determined at pH 6.8 and 7.4. Key findings The Papp values followed this order: BF > HEE > RU (1.77 0.02 > 1.53 0.07 > 0.90 0.03 9 10 5 cm/s). The lowest solubility values followed this order: HEE > RU > BF (2.988 0.07 > 0.205 0.002 > 0.189 0.005 mg/ml). Conclusions According to these results, rutin could be classified as BCS classes III (high solubility/low permeability) and IV (low solubility/low permeability), depending on the plant matrix. Further work needs to be done in order to establish how apply the BCS for research and development of new botanical drugs or for bioequivalence purposes.application/pdfenghttp://creativecommons.org/licenses/by-nc/4.0/Attribution-NonCommercial 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Blackwell Publishing LtdMatrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutinPúblico generalBiopharmaceutics Classification System; Caco-2 cells; permeability; Physalis peruviana; rutin; solubilityinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArtículohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_2df8fbb1BarranquillaFarmaciaSede Norte1. Guidance for Industry. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Silver Spring, MD: CDER/FDA, 2017.2. Ku MS. Use of the biopharmaceutical classification system in early drug development. AAPS J 2008; 10: 208– 212.3. Amidon GL et al. A Theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995; 12: 413–420.4. Broccatelli F et al. BDDCS class prediction for new molecular entities. Mol Pharm 2012; 9: 570–580.5. Mamadou G et al. Increased intestinal permeation and modulation of presystemic metabolism of resveratrol formulated into self-emulsifying drug delivery systems. Int J Pharm 2017; 521: 150–155.6. Li X et al. Improvement of intestinal absorption of curcumin by cyclodextrins and the mechanisms underlying absorption enhancement. Int J Pharm 2018; 535: 340–349.7. Waldmann S et al. Provisional biopharmaceutical classification of some common herbs used in western medicine. Mol Pharm 2012; 9: 815–822.8. Fong SYK et al. Establishing the pharmaceutical quality of Chinese herbal medicine: a provisional BCS classification. Mol Pharm 2013; 10: 1623.9. P erez-S anchez A et al. Evaluation of the intestinal permeability of rosemary (Rosmarinus officinalis L.) extract polyphenols and terpenoids in Caco-2 cell monolayers. PLoS ONE 2017; 12: e0172063.10. Li H et al. Establishment of modified biopharmaceutics classification system absorption model for oral Traditional Chinese Medicine (Sanye Tablet). J Ethnopharmacol 2019; 244: 112148.11. Cao X et al. Analysis of five active ingredients of Er-Zhi-Wan, a traditional Chinese medicine water-honeyed pill, using the biopharmaceutics classification system. Biomed Chromatogr 2020; 34: e4757.12. Gao S et al. Highly variable contents of phenolics in St John’s wort products impact their transport in the human intestinal Caco-2 cell model: pharmaceutical and biopharmaceutical rationale for product standardization. J Agric Food Chem 2010; 58: 6650– 6659.13. Rasoanaivo P et al. Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions. Malar J 2011; 10: S4.14. Yang Y et al. Synergy effects of herb extracts: pharmacokinetics and pharmacodynamic basis. Fitoterapia 2014; 92: 133–147.15. Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620–643.16. Li Y et al. In vivo pharmacokinetics comparisons of icariin, emodin and psoralen from Gan-kang granules and extracts of Herba Epimedii, Nepal dock root, Ficus hirta yahl. J Ethnopharmacol 2009; 124: 522–529.17. Kammalla AK et al. Comparative pharmacokinetic interactions of quercetin and rutin in rats after oral administration of European patented formulation containing Hipphophae rhamnoides and co-administration of quercetin and rutin. Eur J Drug Metab Pharmacokinet 2015; 40: 277–284.18. Chua LS. A review on plant-based rutin extraction methods and its pharmacological activities. J Ethnopharmacol 2013; 150: 805–817.19. Gull on B et al. Rutin: a review on extraction, identification and purification methods, biological activities and approaches to enhance its bioavailability. Trends Food Sci Technol 2017; 67: 220–235.20. Ganeshpurkar A, Saluja AK. The pharmacological potential of rutin. Saudi Pharm J 2017; 25: 149–164.21. Ghorbani A. Mechanisms of antidiabetic effects of flavonoid rutin. Biomed Pharmacother 2017; 96: 305– 312.22. Enogieru AB et al. Rutin as a potent antioxidant: Implications for neurodegenerative disorders. Oxid Med Cell Longev 2018; 2018: 6241017.23. Luca SV et al. Bioactivity of dietary polyphenols: the role of metabolites. Crit Rev Food Sci Nutr 2019; 34: 1546669.24. Toro RM. Propuesta de un marcador anal ıtico como herramienta en la microencapsulaci on de un extracto con actividad antioxidante de c alices de Physalis peruviana. Bogot a, Colombia: Universidad Nacional de Colombia, 2014 (dissertation).25. Toro RM et al. Phytochemical analysis, antioxidant and anti-inflammatory activity of calyces from Physalis peruviana. Nat Prod Commun 2014; 9: 1573–1575.26. Cardona MI et al. Influence of extraction process on antioxidant activity and rutin content in Physalis peruviana calyces extract. J Appl Pharm Sci 2017; 7: 164–168.27. Lorenzi H, Matus FJA. Plantas Medicinais no Brasil: nativas e ex oticas, 2nd edn. Sao Paulo, Brasil: Instituto Plantarum de Estudos da Flora LTDA, 2008.28. Matallana et al. eds. Biotecnolog ıa aplicada al mejoramiento de los cultivos de frutas tropicales. Bogot a, Colombia: Universidad Nacional de Colombia, 2010.29. Franco LA et al. Sucrose esters from Physalis peruviana calyces with antiinflammatory activity. Planta Med 2014; 80: 1605–1614.30. Ramadan MF. Bioactive phytochemicals of cape gooseberry (Physalis peruviana L.). In: Murthy H, Bapat V, eds. Bioactive Compounds in Underutilized Fruits and Nuts, Reference Series in Phytochemistry. Cham: Springer, 2019: 1–16.31. Echeverry SM et al. Development and optimization of microparticles containing a hypoglycemic fraction of calyces from Physalis peruviana. J Appl Pharm Sci 2018; 8: 10–18.32. Topic ICH. Q2 (R1). Validation of Analytical Procedures : Text and Methodology. 2005.Geneva: International Conference on Harmonization33. Guidance for Industry. Bioanalytical Method Validation. Silver Spring, MD: CDER/FDA, 2018.34. Kratz JM et al. An HPLC-UV method for the measurement of permeability of marker drugs in the Caco-2 cell assay. Braz J Med Biol Res 2011; 44: 531–537.35. Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 2006; 1: 1112–1116.36. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000; 11(4): 265–283.37. Hubatsch I et al. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protocol 2007; 2: 2111–2119.38. Prince PS, Kamalakkannan N. Rutin improves glucose homeostasis in streptozotocin diabetic tissues by altering glycolytic and gluconeogenic enzymes. J Biochem Mol Toxicol 2006; 20: 96–102.39. Sun H, Pang KS. Permeability, transport, and metabolism of solutes in Caco-2 cell monolayers: a theoretical study. Drug MetabDispos 2008; 36: 102–123.40. Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Rockeville, MD: CDER/FDA, 2005.41. Pollard T, Earnshaw W. Cell Biology, 3rd edn. Amsterdam: Elsevier, 2017.42. Jurasekova Z et al. Effect of pH on the chemical modification of quercetin and structurally related flavonoids characterized by optical (UV-visible and Raman) spectroscopy. Phys Chem Chem Phys 2014; 16: 12802–12811.43. Wang J, XiH Zhao. Degradation kinetics of fisetin and quercetin in solutions affected by medium pH, temperature and co-existing proteins. J Serb Chem Soc 2016; 81: 243–253.44. Yang Y et al. Transport of active flavonoids, based on cytotoxicity and lipophilicity: An evaluation using the blood-brain barrier cell and Caco-2 cell models. Toxicol In Vitro 2014; 28: 388–396.45. Zhang X et al. Absorption and metabolism characteristics of rutin in Caco-2 cells. SciWorld J 2013; 2013: 1–8.46. Andlauer W et al. Intestinal absorption of rutin in free and conjugated forms. Biochem Pharmacol 2001; 62: 369–374.47. Meinl W et al. Sulfotransferase forms expressed in human intestinal Caco-2 and TC7 cells at varying stages of differentiation and role in benzo[a]pyrene metabolism. Drug Metab Dispos 2008; 36: 276–283.48. Ravikumar D et al. Natural flavonoids silymarin and quercetin improve the brain distribution of co-administered P-gp substrate drugs. Springerplus 2016; 5: 1618.49. Zastre J et al. Lack of P-glycoproteinmediated efflux and the potential involvement of an influx transport process contributing to the intestinal uptake of deltamethrin, cis-permethrin, and trans-permethrin. Toxicol Sci 2013; 136: 284–293.50. Wang XX et al. Intestinal absorption of triterpenoids and flavonoids from Glycyrrhizae radix et rhizoma in the human Caco-2 monolayer cell model. Molecules 2017; 22: piiE1627.51. Henriques J et al. Phenolic compounds from Actinidia deliciosa leaves: Caco-2 permeability, enzyme inhibitory activity and cell protein profile studies. J King Saud Univ Sci 2018; 30: 513–518.52. Verjee S et al. Permeation characteristics of hypericin across Caco-2 monolayers in the presence of single flavonoids, defined flavonoid mixtures or Hypericum extract matrix. J Pharm Pharmacol 2017; 12: 12717.53. Boyer J et al. Uptake of quercetin and quercetin 3-glucoside from whole onion and apple peel extracts by Caco-2 cell monolayers. J Agric Food Chem 2004; 52: 7172–7179.54. Ahmad N et al. Rutin-encapsulated chitosan nanoparticles targeted to the brain in the treatment of Cerebral Ischemia. Int J Biol Macromol 2016; 91: 640–655.55. Ahmad N et al. Quantification of rutin in rat’s brain by UHPLC/ESI-QTOF- MS/MS after intranasal administration of rutin loaded chitosan nanoparticles. EXCLI J 2016; 15: 518– 531.56. Boyle SP et al. Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr 2000; 54: 774–782.57. Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine 2009; 16: 97–110.http://purl.org/coar/resource_type/c_6501ORIGINALjphp13248.pdfjphp13248.pdfapplication/pdf551885https://repositorio.uniatlantico.edu.co/bitstream/20.500.12834/974/1/jphp13248.pdf3cc0bc3ce41b7c2d14670af653f2eeefMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8914https://repositorio.uniatlantico.edu.co/bitstream/20.500.12834/974/2/license_rdf24013099e9e6abb1575dc6ce0855efd5MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-81306https://repositorio.uniatlantico.edu.co/bitstream/20.500.12834/974/3/license.txt67e239713705720ef0b79c50b2ececcaMD5320.500.12834/974oai:repositorio.uniatlantico.edu.co:20.500.12834/9742022-11-15 16:19:11.071DSpace de la Universidad de Atlánticosysadmin@mail.uniatlantico.edu.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