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Enhanced bioavailability of verapamil after oral administration with hesperidin in rats

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Abstract

The aim of this study was to investigate the effects of hesperidin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of hesperidin (3 or 10 mg/kg). Compared to the control group, the presence of hesperidin significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 71.1–96.8% and the peak concentration (Cmax) of verapamil by 98.3–105.2%. Hesperidin significantly (p<0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6–49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (Tmax), the elimination rate constant (Kel) and the terminal half-life (T1/2) of verapamil in the presence of hesperidin. The AUC and Cmax of norverapamil were significantly (p<0.05) higher in rats coadministrated with hesperidin than those of the control. Consequently hesperidin significantly enhanced bioavailability of verapamil in rats. These results might be due to the decreased efflux and metabolism of verapamil in the intestine. Drug interactions should be concerned in the clinical setting when verapamil is used concomitantly with hesperidin or hesperidin-containing dietary.

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References

  • Adachi, Y., Suzuki, H., and Sugiyama, Y., Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm. Res., 18, 1660–1668 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Ameer, B., Weintraub, R. A., Johnson, J. V., Yost, R. A., and Rouseff, R. L., Flavanone absorption after naringin, hesperidin, and citrus administration. Clin. Pharmacol. Ther., 60, 34–40 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Bobrowska-Hagerstrand, M., Wrobel, A., Mrowczynska, L., Soderstrom, T., Shirataki, Y., Motohashi, N., Molnar, J., Michalak, K., and Hagerstrand, H., Flavonoids as inhibitors of MRP1-like efflux activity in human erythrocytes. A structure—activity relationship study. Oncol. Res., 13, 463–469 (2003).

    PubMed  Google Scholar 

  • Bok, S. H., Lee, S. H., Park, Y. B., Bae, K. H., Son, K. H., Jeong, T. S., and Choi, M. S., Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methyl-glutaryl-CoA reductase and acyl CoA: cholesterol transferase are lower in rats fed citrus peel extract or a mixture of citrus bioflavonoids. J. Nutr., 129, 1182–1185 (1999).

    PubMed  CAS  Google Scholar 

  • Borradaile, N. M., Carroll, K. K., and Kurowska, E. M., Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin. Lipids., 34, 591–598 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Choi, J. S. and Burm, J. P., Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, a flavonoid, in rabbits. Arch. Pharm. Res., 29, 333–338 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Choi, J. S. and Han, H. K., Pharmacokinetic interaction between diltiazem and morin, a flavonoid, in rats. Pharmacol. Res., 52, 386–391 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Choi, J. S. and Han, H. K., The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. J. Pharm. Pharmacol., 56, 1537–1542 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Doppenschmitt, S., Spahn-Langguth, H., Regardh, C. G., and Langguth, P., Role of P-glycoprotein-mediated secretion in absorptive drug permeability: An approach using passive membrane permeability and affinity to P-glycoprotein. J. Pharm. Sci., 88, 1067–1072 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Eichelbaum, M., Mikus, G., and Vogelgesang, B., Pharmacokinetics of (+)-, (−)-and (±)-verapamil after intravenous administration. Brit. J. Clin. Pharmacol., 17, 453–458 (1984).

    CAS  Google Scholar 

  • Eichelbaum, M., Remberg, E. G., Schomerus, M., and Dengler, H. J., The metabolism of D,L(14C) verapamil in man. Drug Metab. Dispos., 7, 145–148 (1979).

    PubMed  CAS  Google Scholar 

  • Fleckenstein, A., Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann. Rev. Pharmacol. Toxicol., 17, 149–166 (1977).

    Article  CAS  Google Scholar 

  • Fuhr, U., Muller-Peltzer, H., Kern, R., Lopez-Rojas, P., Junemann, M., Harder, S., and Staib A. H. Effects of grapefruit juice and smoking on verapamil concentrations in steady state. Eur. J. Clin. Pharmacol., 58, 45–53 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Garg, A., Garg, S., Zaneveld, L. J. D., and Singla, A. K., Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother. Res., 15, 655–669 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Gottesman, M. M. and Pastan, I., Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem., 62, 385–427 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Gould, B. A., Mann, S., Kieso, H., Bala Subramanian, V., and Raftery, E. B., The 24-hour ambulatory blood pressure profile with verapamil. Circulation., 65, 22–27 (1982).

    PubMed  CAS  Google Scholar 

  • Hodek, P., Trel, P., and Stiborova, M., Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem. Biol. Interact., 139, 1–21 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. J. and Choi, J. S., Effects of naringin on the pharmacokinetics of verapamil and one of its metabolites, norverapamil, in rabbits. Biopharm. Drug. Dispos., 26, 295–300 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Korthuis, R. J. and Gute, D. C., Adhesion molecule expression in postischemic microvascular dysfunction: activity of a micronized purified flavonoid fraction. J. Vasc. Res., 36, 15–23 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Lewis, G. R., Morley, K. D., Lewis, B. M., and Bones, P. J., The treatment of hypertension with verapamil. NZ. Medical. J., 87, 351–354 (1978).

    CAS  Google Scholar 

  • Ross, J. A. and Kasum, C. M., Dietary avonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr., 22, 19–34 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Schomerus, M., Spiegelhaider, B., Stieren, B., and Eichelbaum, M., Physiologic disposition of verapamil in man. Cardiovasc. Res., 10, 605–612 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Tsai, T. H. and Liu, M. C., Determination of extracellular hesperidin in blood and bile of anaesthetized rats by microdialysis with high-performance liquid chromatography: a pharmacokinetic application. J. Chromatogr. B. Analyt. Technol. Biomed. Life. Sci., 806, 161–166 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Yoshiharu, M., Hitomi, T., Hirotami, M., Mikihiko, N., Takashi, T., Hisakazu, O., and Yasufumi, S., Effect of bioflavonoids on vincristine transport across blood-brain barrier. European Journal of Pharmacology., 395, 193–201 (2000).

    Article  Google Scholar 

  • Zhang, S. and Morris, M. E., Effects of the avonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J. Pharmacol. Exp. Ther., 304, 1258–1267 (2003).

    Article  PubMed  CAS  Google Scholar 

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  1. College of Pharmacy, Chosun University, Gwangju, 501-759, Korea

    Yong-Ji Piao & Jun-Shik Choi

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  1. Yong-Ji Piao
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  2. Jun-Shik Choi
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Correspondence to Jun-Shik Choi.

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Piao, YJ., Choi, JS. Enhanced bioavailability of verapamil after oral administration with hesperidin in rats. Arch. Pharm. Res. 31, 518–522 (2008). https://doi.org/10.1007/s12272-001-1187-4

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  • DOI: https://doi.org/10.1007/s12272-001-1187-4

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