Comparative Bioavailability of Two Diosmin Formulations after Oral Administration to Healthy Volunteers

Rosario Russo, Divya Chandradhara, Nunziatina De Tommasi, Rosario Russo, Divya Chandradhara, Nunziatina De Tommasi

Abstract

Diosmin is a flavonoid commonly found in citrus fruits, largely used as adjuvant treatment for circulatory disorders, including chronic venous insufficiency (CVI) and hemorrhoids. Following oral administration, diosmin is not directly absorbed but must first be hydrolyzed into its aglycone, diosmetin, which is then absorbed into the systemic circulation. The aim of the current cross-over clinical study was to assess the pharmacokinetic profile of µSmin® Plus, a micronized diosmin flavonoid complex standardized in diosmin and formulated with a buffering agent (tested formulation). The study compared this to unformulated micronized diosmin (reference), in 16 healthy volunteers. Plasma samples were analyzed by HPLC-MS and plasma diosmetin concentration was measured after deconjugation with β-glucuronidase. For the tested formulation area under the curve (AUC0-t), and maximum plasma and time concentration (Cmax; tmax) were found to be 298.4 ± 163.7, 50.3 ± 22.6 and 2.2 ± 2.9, respectively. AUC0-t and Cmax of the reference were 31.9 ± 100.4 and 2.4 ± 1.9, respectively. The tested formulation showed higher plasmatic concentrations of diosmetin in comparison to those obtained after the administration of unformulated micronized diosmin. The relative bioavailability was 9.4 greater for the tested formulation than in micronized diosmin. In conclusion, our data indicate that µSmin® Plus was rapidly and well absorbed into systemic circulation and may therefore be ideally suitable to deliver diosmin in human interventional trials.

Keywords: chronic venous insufficiency (CVI); diosmetin; diosmin; pharmacokinetics; µSmin® Plus.

Conflict of interest statement

Rosario Russo is employed by Giellepi S.p.A.; he had no influence on the interpretation of study results. No conflict of interest exists for the other authors. Gillepi S.p.A. founded the clinical study.

Figures

Figure 1
Figure 1
Chemical structure of diosmin (A) and diosmetin (B).
Figure 2
Figure 2
LC-MS/MS chromatogram of diosmetin from plasma sample of a treated volunteer.
Figure 3
Figure 3
Plasma concentration time curves of diosmetin after a single oral administration of a tablet containing either µSMIN® Plus or micronized diosmin, in healthy male subjects. Each point represents the mean ± standard deviation (SD) of 16 volunteers.

References

    1. Caristi C., Bellocco E., Panzera V., Toscano G., Vadalà R., Leuzzi U. Flavonoids detection by HPLC-DAD-MS-MS in lemon juices from Sicilian cultivars. J. Agric. Food Chem. 2003;51:3528–3534. doi: 10.1021/jf0262357.
    1. Kanaze F.I., Gabrieli C., Kokkalou E., Georgarakis M., Niopas I. Simultaneous reversed-phase high-performance liquid chromatographic method for the determination of diosmin, hesperidin and naringin in different citrus fruit juices and pharmaceutical formulations. J. Pharm. Biomed. Anal. 2003;33:243–249. doi: 10.1016/S0731-7085(03)00289-9.
    1. Marín F.R., Del Río J.A. Selection of hybrids and edible citrus species with a high content in the diosmin functional compound. Modulating effect of plant growth regulators on contents. J. Agric. Food Chem. 2001;49:3356–3362. doi: 10.1021/jf010052n.
    1. Bush R., Comerota A., Meissner M., Raffetto J.D., Hahn S.R., Freeman K. Recommendations for the medical management of chronic venous disease: The role of Micronized Purified Flavanoid Fraction (MPFF) Phlebology. 2017;32:3–19. doi: 10.1177/0268355517692221.
    1. Garner R.C., Garner J.V., Gregory S., Whattam M., Calam A., Leong D. Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J. Pharm. Sci. 2002;91:32–40. doi: 10.1002/jps.1168.
    1. Patel K., Gadewar M., Tahilyani V., Patel D.K. A review on pharmacological and analytical aspects of diosmetin: A concise report. Chin. J. Integr. Med. 2013;19:792–800. doi: 10.1007/s11655-013-1595-3.
    1. Silvestro L., Tarcomnicu I., Dulea C., Attili N.R., Ciuca V., Peru D., Rizea Savu S. Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry. Anal. Bioanal. Chem. 2013;405:8295–8310. doi: 10.1007/s00216-013-7237-y.
    1. Koutsos A., Tuohy K.M., Lovegrove J.A. Apples and cardiovascular health-is the gut microbiota a core consideration? Nutrients. 2015;7:3959–3998. doi: 10.3390/nu7063959.
    1. Muller M., Zartl B., Schleritzko A., Stenzl M., Viernstein H., Unger F.M. Rhamnosidase activity of selected probiotics and their ability to hydrolyse flavonoid rhamnoglucosides. Bioprocess Biosyst. Eng. 2018;41:221–228. doi: 10.1007/s00449-017-1860-5.
    1. Yang J., Qian D., Jiang S., Shang E.X., Guo J., Duan J.A. Identification of rutin deglycosylated metabolites produced by human intestinal bacteria using UPLC-Q-TOF/MS. J. Chromatogr. B. 2012;898:95–100. doi: 10.1016/j.jchromb.2012.04.024.
    1. Zhang R., Zhang B.L., Xie T., Li G.C., Tuo Y., Xiang Y.T. Biotransformation of rutin to isoquercitrin using recombinant α-L-rhamnosidase from Bifidobacterium breve. Biotechnol. Lett. 2015;37:1257–1264. doi: 10.1007/s10529-015-1792-6.
    1. Bredsdorff L., Nielsen I.L., Rasmussen S.E., Cornett C., Barron D., Bouisset F., Offord E., Williamson G. Absorption, conjugation and excretion of the flavanones, naringenin and hesperetin from alpha-rhamnosidase-treated orange juice in human subjects. Br. J. Nutr. 2010;103:1602–1609. doi: 10.1017/S0007114509993679.
    1. Monti D., Pisvejcová A., Kren V., Lama M., Riva S. Generation of an alpha-L-rhamnosidase library and its application for the selective derhamnosylation of natural products. Biotechnol. Bioeng. 2004;87:763–771. doi: 10.1002/bit.20187.
    1. Zverlov V.V., Hertel C., Bronnenmeier K., Hroch A., Kellermann J., Schwarz W.H. The thermostable alpha-L-rhamnosidase RamA of Clostridium stercorarium: Biochemical characterization and primary structure of a bacterial alpha-L-rhamnoside hydrolase, a new type of inverting glycoside hydrolase. Mol. Microbiol. 2000;35:173–179. doi: 10.1046/j.1365-2958.2000.01691.x.
    1. Serra H., Mendes T., Bronze M.R., Simplício A.L. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg. Med. Chem. 2008;16:4009–4018. doi: 10.1016/j.bmc.2008.01.028.
    1. Freag M.S., Elnaggar Y.S., Abdallah O.Y. Development of novel polymer-stabilized diosmin nanosuspensions: In vitro appraisal and ex vivo permeation. Int. J. Pharm. 2013;454:462–471. doi: 10.1016/j.ijpharm.2013.06.039.
    1. Takahashi A.I., Rebello F.L., Dutra Duque M., Consiglieri V.O., Gomez Ferraz H. Using fluid bed granulation to improve the dissolution of poorly water-soluble drugs. Braz. Arch. Biol. Technol. 2012;55:477–484. doi: 10.1590/S1516-89132012000300020.
    1. Russo R., Mancinelli A., Ciccone M., Terruzzi F., Pisano C., Severino L. Pharmacokinetic profile of µSMIN Plus™, a new micronized diosmin formulation, after oral administration in rats. Nat. Prod. Commun. 2015;10:1569–1572.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅