Skip to main content
Log in

Single Dose Oral and Intravenous Pharmacokinetics and Tissue Distribution of a Novel Hesperetin Derivative MTBH in Rats

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background

MTBH, a novel hesperetin derivative, possesses in vivo hepatoprotective effects against carbon tetrachloride (CCl4)-induced acute liver injury in Institute of Cancer Research (ICR) mice.

Objectives

This study investigated the pharmacokinetics and tissue distribution of MTBH and its conjugated metabolites in rats after a single dose of MTBH.

Methods

Male Sprague–Dawley (SD) rats were orally administered (25, 50, 100 mg/kg) or intravenously administered (25 mg/kg) MTBH and blood samples were withdrawn at specific times. Moreover, after a single oral dose of MTBH (200 mg/kg), tissues (heart, liver, spleen, lung, kidney, stomach, intestine, brain and muscle) were collected at scheduled time points.

Results

The concentration of MTBH in plasma and tissues was assayed by HPLC before and after hydrolysis with β-glucuronidase or sulfatase. The glucuronides/sulfates were extensively present in the plasma, moreover, the free form was detectable in the plasma, but in a small amount equivalent to nearly 0.85–1.46 % of the amount of glucuronides/sulfates, the absolute bioavailability of MTBH was approximately 31.27 %. In tissues, the free form appeared in all tissues examined, with trace amount in brain and muscle, and considerable concentration in stomach and lung. Glucuronides/sulfates were the major forms in intestine, kidney and liver, whereas not detectable in heart, brain and muscle. The liver and intestine were found likely to accumulate MTBH at a high concentration among all tissues.

Conclusions

The free form of MTBH was present in the circulation and all assayed organs, whereas its glucuronides/sulfates were the major forms in plasma and intestine, kidney and liver after a single dose.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Gil-Izquierdo A, Gil MI, Ferreres F. Effect of processing techniques at industrial scale on orange juice antioxidant and beneficial health compounds. J Agric Food Chem. 2002;50(18):5107–14.

    Article  CAS  PubMed  Google Scholar 

  2. Brand W, van der Wel PA, Rein MJ, Barron D, Williamson G, van Bladeren PJ, Rietjens IM. Metabolism and transport of the citrus flavonoid hesperetin in Caco-2 cell monolayers. Drug Metab Dispos. 2008;36(9):1794–802.

    Article  CAS  PubMed  Google Scholar 

  3. Bredsdorff L, Nielsen IL, Rasmussen SE, 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(11):1602–9.

    Article  CAS  PubMed  Google Scholar 

  4. Manach C, Morand C, Gil-Izquierdo A, Bouteloup-Demange C, Remesy C. Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice. Eur J Clin Nutr. 2003;57(2):235–42.

    Article  CAS  PubMed  Google Scholar 

  5. Nielsen IL, Chee WS, Poulsen L, Offord-Cavin E, Rasmussen SE, Frederiksen H, Enslen M, Barron D, Horcajada MN, Williamson G. Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans: a randomized, double-blind, crossover trial. J Nutr. 2006;136(2):404–8.

    CAS  PubMed  Google Scholar 

  6. Bouskela E, Cyrino FZ, Lerond L. Effects of oral administration of different doses of purified micronized flavonoid fraction on microvascular reactivity after ischaemia/reperfusion in the hamster cheek pouch. Br J Pharmacol. 1997;122(8):1611–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miyake Y, Yamamoto K, Tsujihara N, Osawa T. Protective effects of lemon flavonoids on oxidative stress in diabetic rats. Lipids. 1998;33(7):689–95.

    Article  CAS  PubMed  Google Scholar 

  8. Kim JY, Jung KJ, Choi JS, Chung HY. Hesperetin: a potent antioxidant against peroxynitrite. Free Radic Res. 2004;38(7):761–9.

    Article  CAS  PubMed  Google Scholar 

  9. Hirata A, Murakami Y, Shoji M, Kadoma Y, Fujisawa S. Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activity on COX-2 expression. Anticancer Res. 2005;25(5):3367–74.

    CAS  PubMed  Google Scholar 

  10. Galati EM, Monforte MT, Kirjavainen S, Forestieri AM, Trovato A, Tripodo MM. Biological effects of hesperidin, a citrus flavonoid. (Note I): antiinflammatory and analgesic activity. Farmaco. 1994;40(11):709–12.

    CAS  PubMed  Google Scholar 

  11. Paredes A, Alzuru M, Mendez J, Rodriguez-Ortega M. Anti-Sindbis activity of flavanones hesperetin and naringenin. Biol Pharm Bull. 2003;26(1):108–9.

    Article  CAS  PubMed  Google Scholar 

  12. Borradaile NM, Carroll KK, Kurowska EM. Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin. Lipids. 1999;34(6):591–8.

    Article  CAS  PubMed  Google Scholar 

  13. Kim HK, Jeong TS, Lee MK, Park YB, Choi MS. Lipid-lowering efficacy of hesperetin metabolites in high-cholesterol fed rats. Clin Chim Acta. 2003;327(1–2):129–37.

    Article  CAS  PubMed  Google Scholar 

  14. Garg A, Garg S, Zaneveld LJ, Singla AK. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. 2001;15(8):655–69.

    Article  CAS  PubMed  Google Scholar 

  15. Yang M, Tanaka T, Hirose Y, Deguchi T, Mori H, Kawada Y. Chemopreventive effects of diosmin and hesperidin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in male ICR mice. Int J Cancer. 1997;73(5):719–24.

    Article  CAS  PubMed  Google Scholar 

  16. So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer. 1996;26(2):167–81.

    Article  CAS  PubMed  Google Scholar 

  17. Tanaka T, Makita H, Kawabata K, Mori H, Kakumoto M, Satoh K, Hara A, Sumida T, Tanaka T, Ogawa H. Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin. Carcinogenesis. 1997;18(5):957–65.

    Article  CAS  PubMed  Google Scholar 

  18. Miyagi Y, Om AS, Chee KM, Bennink MR. Inhibition of azoxymethane-induced colon cancer by orange juice. Nutr Cancer. 2000;36(2):224–9.

    Article  CAS  PubMed  Google Scholar 

  19. Buckshee K, Takkar D, Aggarwal N. Micronized flavonoid therapy in internal hemorrhoids of pregnancy. Int J Gynaecol Obstet. 1997;57(2):145–51.

    Article  CAS  PubMed  Google Scholar 

  20. Tsimoyiannis EC, Floras G, Antoniou N, Papanikolaou N, Siakas P, Tassis A. Low-molecular-weight heparins and Daflon for prevention of postoperative thromboembolism. World J Surg. 1996;20(8):968–71 (discussion 72).

    Article  CAS  PubMed  Google Scholar 

  21. Maiti K, Mukherjee K, Murugan V, Saha BP, Mukherjee PK. Exploring the effect of Hesperetin–HSPC complex–a novel drug delivery system on the in vitro release, therapeutic efficacy and pharmacokinetics. AAPS PharmSciTech. 2009;10(3):943–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr. 2007;61(4):472–7.

    CAS  PubMed  Google Scholar 

  23. Hackett AM, Marsh I, Barrow A, Griffiths LA. The biliary excretion of flavanones in the rat. Xenobiotica. 1979;9(8):491–501.

    Article  CAS  PubMed  Google Scholar 

  24. Bokkenheuser VD, Shackleton CH, Winter J. Hydrolysis of dietary flavonoid glycosides by strains of intestinal Bacteroides from humans. Biochem J. 1987;248(3):953–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hollman PC, Bijsman MN, van Gameren Y, Cnossen EP, de Vries JH, Katan MB. The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man. Free Radic Res. 1999;31(6):569–73.

    Article  CAS  PubMed  Google Scholar 

  26. Felgines C, Texier O, Morand C, Manach C, Scalbert A, Regerat F, Remesy C. Bioavailability of the flavanone naringenin and its glycosides in rats. Am J Physiol Gastrointest Liver Physiol. 2000;279(6):G1148–54.

    CAS  PubMed  Google Scholar 

  27. Erlund I, Meririnne E, Alfthan G, Aro A. Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice. J Nutr. 2001;131(2):235–41.

    CAS  PubMed  Google Scholar 

  28. Li YM, Li XM, Li GM, Du WC, Zhang J, Li WX, Xu J, Hu M, Zhu Z. In vivo pharmacokinetics of hesperidin are affected by treatment with glucosidase-like BglA protein isolated from yeasts. J Agric Food Chem. 2008;56(14):5550–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Matsumoto H, Ikoma Y, Sugiura M, Yano M, Hasegawa Y. Identification and quantification of the conjugated metabolites derived from orally administered hesperidin in rat plasma. J Agric Food Chem. 2004;52(21):6653–9.

    Article  CAS  PubMed  Google Scholar 

  30. Mullen W, Archeveque MA, Edwards CA, Matsumoto H, Crozier A. Bioavailability and metabolism of orange juice flavanones in humans: impact of a full-fat yogurt. J Agric Food Chem. 2008;56(23):11157–64.

    Article  CAS  PubMed  Google Scholar 

  31. Brett GM, Hollands W, Needs PW, Teucher B, Dainty JR, Davis BD, Brodbelt JS, Kroon PA. Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion. Br J Nutr. 2009;101(5):664–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ameer B, Weintraub RA, Johnson JV, Yost RA, Rouseff RL. Flavanone absorption after naringin, hesperidin, and citrus administration. Clin Pharmacol Ther. 1996;60(1):34–40.

    Article  CAS  PubMed  Google Scholar 

  33. Griffiths LA, Barrow A. Metabolism of flavonoid compounds in germ-free rats. Biochem J. 1972;130(4):1161–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Manach C, Morand C, Demigne C, Texier O, Regerat F, Remesy C. Bioavailability of rutin and quercetin in rats. FEBS Lett. 1997;409(1):12–6.

    Article  CAS  PubMed  Google Scholar 

  35. O’Leary KA, Day AJ, Needs PW, Sly WS, O’Brien NM, Williamson G. Flavonoid glucuronides are substrates for human liver beta-glucuronidase. FEBS Lett. 2001;503(1):103–6.

    Article  PubMed  Google Scholar 

  36. Pasqualini JR, Chetrite GS. Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol. 2005;93(2–5):221–36.

    Article  CAS  PubMed  Google Scholar 

  37. Reed MJ, Purohit A, Woo LW, Newman SP, Potter BV. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev. 2005;26(2):171–202.

    Article  CAS  PubMed  Google Scholar 

  38. Takumi H, Mukai R, Ishiduka S, Kometani T, Terao J. Tissue distribution of hesperetin in rats after a dietary intake. Biosci Biotechnol Biochem. 2011;75(8):1608–10.

    Article  CAS  PubMed  Google Scholar 

  39. Hiermann A, Schramm HW, Laufer S. Anti-inflammatory activity of myricetin-3-O-beta-d-glucuronide and related compounds. Inflamm Res. 1998;47(11):421–7.

    Article  CAS  PubMed  Google Scholar 

  40. Moon JH, Tsushida T, Nakahara K, Terao J. Identification of quercetin 3-O-beta-d-glucuronide as an antioxidative metabolite in rat plasma after oral administration of quercetin. Free Radic Biol Med. 2001;30(11):1274–85.

    Article  CAS  PubMed  Google Scholar 

  41. Manach C, Morand C, Crespy V, Demigne C, Texier O, Regerat F, Remesy C. Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett. 1998;426(3):331–6.

    Article  CAS  PubMed  Google Scholar 

  42. Shirai M, Kawai Y, Yamanishi R, Kinoshita T, Chuman H, Terao J. Effect of a conjugated quercetin metabolite, quercetin 3-glucuronide, on lipid hydroperoxide-dependent formation of reactive oxygen species in differentiated PC-12 cells. Free Radic Res. 2006;40(10):1047–53.

    Article  CAS  PubMed  Google Scholar 

  43. Yang JH, Hsia TC, Kuo HM, Chao PD, Chou CC, Wei YH, Chung JG. Inhibition of lung cancer cell growth by quercetin glucuronides via G2/M arrest and induction of apoptosis. Drug Metab Dispos. 2006;34(2):296–304.

    Article  CAS  PubMed  Google Scholar 

  44. Yoshino S, Hara A, Sakakibara H, Kawabata K, Tokumura A, Ishisaka A, Kawai Y, Terao J. Effect of quercetin and glucuronide metabolites on the monoamine oxidase-A reaction in mouse brain mitochondria. Nutrition. 2011;27(7–8):847–52.

    Article  CAS  PubMed  Google Scholar 

  45. Trinh HT, Joh EH, Kwak HY, Baek NI, Kim DH. Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice. Acta Pharmacol Sin. 2010;31(6):718–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This project was supported by the National Science Foundation of China (Nos: 81273526, and 81473268), Anhui provincial key Scientific and technological project (1301042212), Anhui Provincial Natural Science Foundation (1308085MH145), Specialized Research Fund for the Doctoral Program of Higher Education (20123420120001).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jun Li.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, C., Qian, Z., Chen, R. et al. Single Dose Oral and Intravenous Pharmacokinetics and Tissue Distribution of a Novel Hesperetin Derivative MTBH in Rats. Eur J Drug Metab Pharmacokinet 41, 675–688 (2016). https://doi.org/10.1007/s13318-015-0293-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-015-0293-2

Keywords

Navigation