The pharmacokinetic profile and tissue uptake of daidzein (DAI) was determined in rat serum and tissues (lungs, eyes, brain, heart, spleen, fat, liver, kidney, and testes) after intravenous and intraperitoneal administration of DAI in suspension or complexed with ethylenediamine-modified γ-cyclodextrin (GCD-EDA/DAI). The absolute and relative bioavailability of DAI suspended (20 mg/kg i.v. vs. 50 mg/kg i.p.) and complexed (0.54 mg/kg i.v. vs. 1.35 mg/kg i.p.) was determined. After i.p. administration, absorption of DAI complexed with GCD-EDA was more rapid (tmax = 15 min) than that of DAI in suspension (tmax = 45 min) with a ca. 3.6 times higher maximum concentration (Cmax = 615 vs. 173 ng/mL). The i.v. half-life of DAI was longer in GCD-EDA/DAI complex compared with DAI in suspension (t0.5 = 380 min vs. 230 min). The volume of distribution of DAI given i.v. in GCD-EDA/DAI complex was ca. 6 times larger than DAI in suspension (38.6 L/kg vs. 6.2 L/kg). Our data support the concept that the pharmacokinetics of DAI suspended in high doses are nonlinear. Increasing the intravenous dose 34 times resulted in a 5-fold increase in AUC. In turn, increasing the intraperitoneal dose 37 times resulted in a ca. 2-fold increase in AUC. The results of this study suggested that GCD-EDA complex may improve DAI bioavailability after i.p. administration. The absolute bioavailability of DAI in GCD-EDA inclusion complex was ca. 3 times greater (F = 82.4% vs. 28.2%), and the relative bioavailability was ca. 21 times higher than that of DAI in suspension, indicating the need to study DAI bioavailability after administration by routes other than intraperitoneal, e.g., orally, subcutaneously, or intramuscularly. The concentration of DAI released from GCD-EDA/DAI inclusion complex to all the rat tissues studied was higher than after administration of DAI in suspension. The concentration of DAI in brain and lungs was found to be almost 90 and 45 times higher, respectively, when administered in complex compared to the suspended DAI. Given the nonlinear relationship between DAI bioavailability and the dose released from the GCD-EDA complex, complexation of DAI may thus offer an effective approach to improve DAI delivery for treatment purposes, for example in mucopolysaccharidosis (MPS), allowing the reduction of ingested DAI doses.

Chair and Department of Toxicology Jagiellonian University Medical College Faculty of Pharmacy Medyczna 9 30 688 Kraków Poland

Department of Inorganic and Analytical Chemistry Jagiellonian University Medical College Faculty of Pharmacy Medyczna 9 30 688 Kraków Poland

Department of Pharmacology Faculty of Medicine Masaryk University Kamenice 5 Brno 625 00 Czech Republic

Faculty of Chemistry Jagiellonian University Gronostajowa 2 30 387 Kraków Poland

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Clarkson T.B. Soy, soy phytoestrogens and cardiovascular disease. J. Nutr. 2002;132:566S–569S. doi: 10.1093/jn/132.3.566S. PubMed DOI

Mahmoud A.M., Yang W., Bosland M.C. Soy isoflavones and prostate cancer: A review of molecular mechanisms. J. Steroid Biochem. Mol. Biol. 2014;140:116–132. doi: 10.1016/j.jsbmb.2013.12.010. PubMed DOI PMC

Hua F., Li C.-H., Chen X.-G., Liu X.-P. Daidzein exerts anticancer activity towards SKOV3 human ovarian cancer cells by inducing apoptosis and cell cycle arrest, and inhibiting the Raf/MEK/ERK cascade. Int. J. Mol. Med. 2018;41:3485–3492. doi: 10.3892/ijmm.2018.3531. PubMed DOI

Liang Y.-S., Qi W.-T., Guo W., Wang C.-L., Hu Z.-B., Li A.-K. Genistein and daidzein induce apoptosis of colon cancer cells by inhibiting the accumulation of lipid droplets. Food Nutr. Res. 2018;62:1384. doi: 10.29219/fnr.v62.1384. PubMed DOI PMC

Chen Z., Miao H., Zhu Z., Zhang H., Huang H. Daidzein induces apoptosis of non-small cell lung cancer cells by restoring STK4/YAP1 signaling. Int. J. Clin. Exp. Med. 2017;10:15205–15212.

Bao C., Namgung H., Lee J., Park H.-C., Ko J., Moon H., Ko H.W., Lee H.J. Daidzein suppresses tumor necrosis factor-α induced migration and invasion by inhibiting hedgehog/gli1 signaling in human breast cancer cells. J. Agric. Food Chem. 2014;62:3759–3767. doi: 10.1021/jf500231t. PubMed DOI

He Y., Wu X., Cao Y., Hou Y., Chen H., Wu L., Lu L., Zhu W., Gu Y. Daidzein exerts anti-tumor activity against bladder cancer cells via inhibition of FGFR3 pathway. Neoplasma. 2016;63:523–531. doi: 10.4149/neo_2016_405. PubMed DOI

Shim S.H. 20S proteasome inhibitory activity of flavonoids isolated from Spatholobus suberectus. Phyther. Res. 2011;25:615–618. doi: 10.1002/ptr.3342. PubMed DOI

Fujitaka Y., Shimoda K., Araki M., Doi S., Ono T., Hamada H., Hamada H. Biotransformation of daidzein to diadzein-7-glucoside and its anti-allergic activity. Nat. Prod. Commun. 2017;12:1741–1742. doi: 10.1177/1934578X1701201121. DOI

Das D., Sarkar S., Bordoloi J., Wann S.B., Kalita J., Manna P. Daidzein, its effects on impaired glucose and lipid metabolism and vascular inflammation associated with type 2 diabetes. BioFactors. 2018;44:407–417. doi: 10.1002/biof.1439. PubMed DOI

Peng Y., Shi Y., Zhang H., Mine Y., Tsao R. Anti-inflammatory and anti-oxidative activities of daidzein and its sulfonic acid ester derivatives. J. Funct. Foods. 2017;35:635–640. doi: 10.1016/j.jff.2017.06.027. DOI

Roghani M., Vaez Mahdavi M.-R., Jalali-Nadoushan M.-R., Baluchnejadmojarad T., Naderi G., Roghani-Dehkordi F., Taghi Joghataei M., Kord M. Chronic administration of daidzein, a soybean isoflavone, improves endothelial dysfunction and attenuates oxidative stress in streptozotocin- induced diabetic rats. Phyther. Res. 2013;27:112–117. doi: 10.1002/ptr.4699. PubMed DOI

Vitale D.C., Piazza C., Melilli B., Drago F., Salomone S. Isoflavones: Estrogenic activity, biological effect and bioavailability. Eur. J. Drug Metab. Pharmacokinet. 2013;38:15–25. doi: 10.1007/s13318-012-0112-y. PubMed DOI

Zhi C.D., Lowik C. Dose-dependent effects of phytoestrogens on bone. Trends Endocrinol. Metab. 2005;16:207–213. doi: 10.1016/j.tem.2005.05.001. PubMed DOI

Zhao L., Mao Z., Brinton R.D. A select combination of clinically relevant phytoestrogens enhances estrogen receptor β-binding Selectivity and neuroprotective activities in vitro and in vivo. Endocrinology. 2009;150:770–783. doi: 10.1210/en.2008-0715. PubMed DOI

Zheng X., Lee S.-K., Chun O.K. Soy Isoflavones and Osteoporotic Bone Loss: A Review with an Emphasis on Modulation of Bone Remodeling. J. Med. Food. 2016;19:1–14. doi: 10.1089/jmf.2015.0045. PubMed DOI PMC

Prasain J.K., Jones K., Brissie N., Moore R., Wyss J.M., Barnes S. Identification of puerarin and its metabolites in rats by liquid chromatography-tandem mass spectrometry. J. Agric. Food Chem. 2004;52:3708–3712. doi: 10.1021/jf040037t. PubMed DOI

Ko Y.-H., Kwon S.-H., Ma S.-X., Seo J.-Y., Lee B.-R., Kim K., Kim S.Y., Lee S.-Y., Jang C.-G. The memory-enhancing effects of 7,8,4′-trihydroxyisoflavone, a major metabolite of daidzein, are associated with activation of the cholinergic system and BDNF signaling pathway in mice. Brain Res. Bull. 2018;142:197–206. doi: 10.1016/j.brainresbull.2018.07.012. PubMed DOI

Zeng S., Tai F., Zhai P., Yuan A., Jia R., Zhang X. Effect of daidzein on anxiety, social behavior and spatial learning in male Balb/cJ mice. Pharmacol. Biochem. Behav. 2010;96:16–23. doi: 10.1016/j.pbb.2010.03.015. PubMed DOI

Arfi A., Richard M., Gandolphe C., Scherman D. Storage correction in cells of patients suffering from mucopolysaccharidoses types IIIA and VII after treatment with genistein and other isoflavones. J. Inherit. Metab. Dis. 2010;33:61–67. doi: 10.1007/s10545-009-9029-2. PubMed DOI

Kloska A., Jakóbkiewicz-Banecka J., Narajczyk M., Banecka-Majkutewicz Z., Wȩgrzyn G. Effects of flavonoids on glycosaminoglycan synthesis: Implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses. Metab. Brain Dis. 2011;26:1–8. doi: 10.1007/s11011-011-9233-2. PubMed DOI PMC

Piotrowska E., Jakóbkiewicz-Banecka J., Barańska S., Tylki-Szymańska A., Czartoryska B., Wegrzyn A., Wegrzyn G. Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur. J. Hum. Genet. 2006;14:846–852. doi: 10.1038/sj.ejhg.5201623. PubMed DOI

Piotrowska E., Jakóbkiewicz-Banecka J., Tylki-Szymanska A., Liberek A., Maryniak A., Malinowska M., Czartoryska B., Puk E., Kloska A., Liberek T., et al. Genistin-rich soy isoflavone extract in substrate reduction therapy for Sanfilippo syndrome: An open-label, pilot study in 10 pediatric patients. Curr. Ther. Res.-Clin. Exp. 2008;69:166–179. doi: 10.1016/j.curtheres.2008.04.002. PubMed DOI PMC

Piotrowska E., Jakóbkiewicz-Banecka J., Wȩgrzyn G. Different amounts of isoflavones in various commercially available soy extracts in the light of gene expression-targeted isoflavone therapy. Phyther. Res. 2010;24:S109–S113. doi: 10.1002/ptr.2944. PubMed DOI

Moskot M., Jakóbkiewicz-Banecka J., Kloska A., Smolińska E., Mozolewski P., Malinowska M., Rychłowski M., Banecki B., Wȩgrzyn G., Gabig-Cimińska M. Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids. Sci. Rep. 2015;5 doi: 10.1038/srep09378. PubMed DOI PMC

Friso A., Tomanin R., Salvalaio M., Scarpa M. Genistein reduces glycosaminoglycan levels in a mouse model of mucopolysaccharidosis type II. Br. J. Pharmacol. 2010;159:1082–1091. doi: 10.1111/j.1476-5381.2009.00565.x. PubMed DOI PMC

The European Union Clinical Trials High Dose Genistein in Sanfilippo Syndrome. [(accessed on 11 February 2020)]; Available online: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-001479-18/GB.

Lavery C., Hendriksz C.J., Jones S.A. Mortality in patients with Sanfilippo syndrome. Orphanet J. Rare Dis. 2017;12:168. doi: 10.1186/s13023-017-0717-y. PubMed DOI PMC

Nan G., Shi J., Huang Y., Sun J., Lv J., Yang G., Li Y. Dissociation Constants and Solubilities of Daidzein and Genistein in Different Solvents. J. Chem. Eng. Data. 2014;59:1304–1311. doi: 10.1021/je4010905. DOI

Amawi H., Ashby C.R., Jr., Tiwari A.K. Cancer chemoprevention through dietary flavonoids: What’s limiting? Chin. J. Cancer. 2017;36:50. doi: 10.1186/s40880-017-0217-4. PubMed DOI PMC

Setchell K.D.R., Faughnan M.S., Avades T., Zimmer-Nechemias L., Brown N.M., Wolfe B.E., Brashear W.T., Desai P., Oldfield M.F., Botting N.P., et al. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am. J. Clin. Nutr. 2003;77:411–419. doi: 10.1093/ajcn/77.2.411. PubMed DOI

Setchell K.D.R., Brown N.M., Desai P., Zimmer-Nechemias L., Wolfe B.E., Brashear W.T., Kirschner A.S., Cassidy A., Heubi J.E. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J. Nutr. 2001;131:1362S–1375S. doi: 10.1093/jn/131.4.1362S. PubMed DOI

Fairley B., Botting N.P., Cassidy A. The synthesis of daidzein sulfates. Tetrahedron. 2003;59:5407–5410. doi: 10.1016/S0040-4020(03)00869-X. DOI

Kanakubo A., Koga K., Isobe M., Fushimi T., Saitoh T., Ohshima Y., Tsukamoto Y. First finding of Daidzein 7-O-phosphate and Genistein 7-O-phosphate that are hydrolyzed by sulfatase. Tetrahedron. 2001;57:8801–8805. doi: 10.1016/S0040-4020(01)00863-8. DOI

Needs P.W., Williamson G. Syntheses of daidzein-7-yl β-d-glucopyranosiduronic acid and daidzein-4′,7-yl di-β-d-glucopyranosiduronic acid. Carbohydr. Res. 2001;330:511–515. doi: 10.1016/S0008-6215(00)00326-8. PubMed DOI

Del Gaudio P., Russo P., Rodriguez Dorado R., Sansone F., Mencherini T., Gasparri F., Aquino R.P. Submicrometric hypromellose acetate succinate particles as carrier for soy isoflavones extract with improved skin penetration performance. Carbohydr. Polym. 2017;165:22–29. doi: 10.1016/j.carbpol.2017.02.025. PubMed DOI

Del Gaudio P., Sansone F., Mencherini T., De Cicco F., Russo P., Aquino R.P. Nanospray Drying as a Novel Tool to Improve Technological Properties of Soy Isoflavone Extracts. Planta Med. 2017;83:426–433. doi: 10.1055/s-0042-110179. PubMed DOI

Zou T., Gu L. TPGS emulsified zein nanoparticles enhanced oral bioavailability of daidzin: In vitro characteristics and in vivo performance. Mol. Pharm. 2013;10:2062–2070. doi: 10.1021/mp400086n. PubMed DOI

Huang P.-H., Hu S.C., Lee C.-W., Yeh A.-C., Tseng C.-H., Yen F.-L. Design of acid-responsive polymeric nanoparticles for 7, 3′, 4′-trihydroxyisoflavone topical administration. Int. J. Nanomed. 2016;11:1615–1627. doi: 10.2147/IJN.S100418. PubMed DOI PMC

Kumara N.R.R., Madhusudhan B. Evaluation of anticancer efficacy of daidzein-loaded poly(D, L) lactic acid nanoparticles. J. Bionanosci. 2011;5:122–129. doi: 10.1166/jbns.2011.1061. DOI

Zhao C., Wang Y., Su Y., Zhang H., Ding L., Yan X., Zhao D., Shao N., Ye X., Cheng Y. Inclusion complexes of isoflavones with two commercially available dendrimers: Solubility, stability, structures, release behaviors, cytotoxicity, and anti-oxidant activities. Int. J. Pharm. 2011;421:301–309. doi: 10.1016/j.ijpharm.2011.09.044. PubMed DOI

Yang Z., Xie J., Zhou W., Shi W. Temperature sensitivity and drug encapsulation of star-shaped amphiphilic block copolymer based on dendritic poly(ether-amide) J. Biomed. Mater. Res.-Part. A. 2009;89:988–1000. doi: 10.1002/jbm.a.31881. PubMed DOI

Panizzon G.P., Bueno F.G., Ueda-Nakamura T., Nakamura C.V., Filho B.P.D. Preparation of spray-dried soy isoflavone-loaded gelatin microspheres for enhancement of dissolution: Formulation, characterization and in vitro evaluation. Pharmaceutics. 2014;6:599–615. doi: 10.3390/pharmaceutics6040599. PubMed DOI PMC

Ge Y.-B., Chen D.-W., Xie L.-P., Zhang R. Optimized preparation of daidzein-loaded chitosan microspheres and in vivo evaluation after intramuscular injection in rats. Int. J. Pharm. 2007;338:142–151. doi: 10.1016/j.ijpharm.2007.01.046. PubMed DOI

Daruházi Á.E., Kiss T., Vecsernyés M., Szente L., Szoke T., Lemberkovics T. Investigation of transport of genistein, daidzein and their inclusion complexes prepared with different cyclodextrins on Caco-2 cell line. J. Pharm. Biomed. Anal. 2013;84:112–116. doi: 10.1016/j.jpba.2013.05.012. PubMed DOI

Li S., Yuan L., Chen Y., Zhou W., Wang X. Studies on the inclusion complexes of daidzein with β-cyclodextrin and derivatives. Molecules. 2017;22:2183. doi: 10.3390/molecules22122183. PubMed DOI PMC

Rungrotmongkol T., Chakcharoensap T., Pongsawasdi P., Kungwan N., Wolschann P. The inclusion complexation of daidzein with β-cyclodextrin and 2,6-dimethyl-β-cyclodextrin: A theoretical and experimental study. Monatshefte fur Chemie. 2018;149:1739–1747. doi: 10.1007/s00706-018-2209-8. DOI

Deng Y.-H., Su L.-N., Pang Y.-H., Guo Y.-F., Wang F., Liao X.-L., Yang B., Wand F., Liao X.-L., Yang B. Preparation, Characterization and Water Solubility of Inclusion Complexes of Daidzein with Amino-Modified β-Cyclodextrins. Chin. J. Anal. Chem. 2017;45:648–653. doi: 10.1016/S1872-2040(17)61012-0. DOI

Fumić B., Jablan J., Cinčić D., Zovko Končić M., Jug M. Cyclodextrin encapsulation of daidzein and genistein by grinding: Implication on the glycosaminoglycan accumulation in mucopolysaccharidosis type II and III fibroblasts. J. Microencapsul. 2018;35:1–12. doi: 10.1080/02652048.2017.1409819. PubMed DOI

Kamiński K., Kujdowicz M., Kajta M., Nowakowska M., Szczubiałka K. Enhanced delivery of daidzein into fibroblasts and neuronal cells with cationic derivatives of gamma-cyclodextrin for the control of cellular glycosaminoglycans. Eur. J. Pharm. Biopharm. 2015;91:111–119. doi: 10.1016/j.ejpb.2015.02.002. PubMed DOI

EMA . Guideline on Bioanalytical Method Validation Guideline on Bioanalytical Method Validation Table of Contents. EMA; Amsterdam, The Netherlands: 2012.

Xu X., Wang H.J., Murphy P.A., Cook L., Hendrich S. Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. J. Nutr. 1994;124:825–832. doi: 10.1093/jn/124.6.825. PubMed DOI

Karr S.C., Lampe J.W., Hutchins A.M., Slavin J.L. Urinary isoflavonoid excretion in humans is dose dependent at low to moderate levels of soy-protein consumption. Am. J. Clin. Nutr. 1997;66:46–51. doi: 10.1093/ajcn/66.1.46. PubMed DOI

Wakai K., Egami I., Kato K., Kawamura T., Tamakoshi A., Nakayama T., Wada M., Ohno Y. Dietary intake and sources of isoflavones among Japanese. Nutr. Cancer. 1999;33:139–145. doi: 10.1207/S15327914NC330204. PubMed DOI