Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition

Bhargavi Latha Athukuri; Prasad Neerati

doi:10.1515/dmpt-2016-0029

Article

Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition

Bhargavi Latha Athukuri and Prasad Neerati

Published/Copyright: November 22, 2016

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information

From the journal Drug Metabolism and Personalized Therapy Volume 31 Issue 4

Abstract

Background:

Cytochrome P450-2D6 (CYP2D6), a member of the CYP450 mixed function oxidase system, is an important CYP isoform with regard to herbal-drug interactions and is responsible for the metabolism of nearly 25% of drugs. Until now, studies on the effects of various phytochemicals on CYP2D6 activity in vivo have been very rare. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. In the present study, the effects of gallic acid and ellagic acid pretreatment on intestinal transport and oral bioavailability of metoprolol were investigated.

Methods:

The intestinal transport of metoprolol was assessed by conducting an in situ single pass intestinal perfusion (SPIP) study. The bioavailability study was conducted to evaluate the pharmacokinetic parameters of orally administered metoprolol in rats.

Results:

After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of metoprolol was observed at the ileum part of rat intestine. A significant improvement in the peak plasma concentration (C_max) and area under the serum concentration–time profile (AUC) and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid.

Conclusions:

Gallic acid and ellagic acid significantly enhanced the oral bioavailability of metoprolol by inhibiting CYP2D6-mediated metabolism in the rat liver. Hence, adverse herbal-drug interactions may result with concomitant ingestion of gallic acid and ellagic acid supplements and drugs that are CYP2D6 substrates. The clinical assessment of these interactions should be further investigated in human volunteers.

Keywords: cytochrome P450; ellagic acid; gallic acid; metoprolol; quinidine

Acknowledgments

The authors would like thank the University Grants Commission (UGC) Research Fellowship in Sciences to meritorious Students, New Delhi, and (F.No.7-106/2007. BSR) and Mr. Ramesh Gannu of AET Technology, Hyderabad, for calculating pharmacokinetic data using Phoenix WinNonLin 6.2 software.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Hermann R, Richter O. Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions. Planta Medica 2012;78:1458–77.10.1055/s-0032-1315117Search in Google Scholar PubMed

2. Yamsani SK, Devandla A, Dharani S, Gannu R, Athukuri BL, Palem CR, et al. P-Glycoprotein- and cytochrome P-450-mediated herbal drug Interactions. Drug Metab Drug Interact 2010;25:3–16.10.1515/DMDI.2010.006Search in Google Scholar

3. Claudine M, Augustin S, Christine M, Christian R, Liliana J. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79:727–47.10.1093/ajcn/79.5.727Search in Google Scholar PubMed

4. An-Na L, Sha L, Yu-Jie Z, Xiang-Rong X, Yu-Ming C, Hua-Bin Li. Resources and biological activities of natural polyphenols. Nutrients 2014;6:6020–47.10.3390/nu6126020Search in Google Scholar PubMed PubMed Central

5. Mansouri MT, Soltani M, Naghizadeh B, Farbood Y, Mashak A, Sarkaki A. A possible mechanism for the anxiolytic-like effect of gallic acid in the rat elevated plus maze. Pharmacol Biochem Behav 2013;117:40–6.10.1016/j.pbb.2013.12.011Search in Google Scholar PubMed

6. Kim YS, Zerin T, Song HY. Antioxidant action of ellagic acid ameliorates paraquat-induced A549 cytotoxicity. Biol Pharm Bull 2013;36:609–15.10.1248/bpb.b12-00990Search in Google Scholar PubMed

7. Thangavel MV, Ramasamy MK, Aruna A, Govind PD, Kaliappan I. Comparative inhibitory potential of selected dietary bioactive polyphenols, phytosterols on CYP3A4 and CYP2D6 with fluorometric high-throughput screening. J Food Sci Technol 2015;52:4537–43.10.1007/s13197-014-1472-xSearch in Google Scholar PubMed PubMed Central

8. Wacher VJ, Benet ZL. Use of gallic acid esters to increase bioavailability of orally administered pharmaceutical compounds. U.S. Patent US 6180666 B1; 2001.Search in Google Scholar

9. Giftson SJ, Jayanthi S, Viswanathan P, Umadevi P, Nalini N. Effect of gallic acid on xenobiotic metabolizing enzymes in 1,2-dimethyl hydrazine induced colon carcinogenesis in Wistar rats–a chemopreventive approach. Food Chem Toxicol 2011;49:887–92.10.1016/j.fct.2010.12.012Search in Google Scholar PubMed

10. Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF. New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metab Rev 2009;41:573–643.10.1080/03602530903118729Search in Google Scholar PubMed

11. Sutton SC, Rinaldi MT, Vukovinsky KE. Comparison of the gravimetric, phenol red and 14C-PEG-3350 methods to determine water absorption in the rat single-pass intestinal perfusion model. AAPS Pharm Sci 2001;3:93–7.10.1208/ps030325Search in Google Scholar PubMed PubMed Central

12. Varma MV, Panchagnula R. Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability. J Pharm Sci 2005;94:1694–704.10.1002/jps.20309Search in Google Scholar PubMed

13. Prasad N, Satish KB. Effect of diosmin on the intestinal absorption and pharmacokinetics of fexofenadine in rats. Pharmacol Rep 2015;67:339–44.10.1016/j.pharep.2014.09.010Search in Google Scholar PubMed

14. Mahvash I, Shoba RH. Estimation of metoprolol in human plasma by HPLC method. Int J Pharm Pharm Sci 2015;7:442–46.Search in Google Scholar

15. Salphati L, Childers K, Pan L, Tsutsui K, Takahashi L. Evaluation of a single-pass intestinal-perfusion method in rat for the prediction of absorption in man. J Pharm Pharmacol 2001;53:1007–13.10.1211/0022357011776252Search in Google Scholar PubMed

16. Ekaterina AK. Effect of natural polyphenols on CYP metabolism: implications for diseases. Chem Res Toxicol 2015;28:1359–90.10.1021/acs.chemrestox.5b00121Search in Google Scholar PubMed

17. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5:6–13.10.1038/sj.tpj.6500285Search in Google Scholar PubMed

18. Bramer SL, Suri A. Inhibition of CYP2D6 by quinidine and its effects on the metabolism of cilostazol. Clin Pharmacokinet 1999;37:41–51.10.2165/00003088-199937002-00005Search in Google Scholar PubMed

19. Ponnusankar S, Subrata P, Ramesh B, Arun B, Pulok KM. Cytochrome P450 inhibitory potential of Triphala–A Rasayana from Ayurveda. J Ethnopharmacol 2011;133:120–5.10.1016/j.jep.2010.09.022Search in Google Scholar PubMed

Received: 2016-9-9

Accepted: 2016-11-1

Published Online: 2016-11-22

Published in Print: 2016-12-1

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/dmpt-2016-0029

Keywords for this article

cytochrome P450; ellagic acid; gallic acid; metoprolol; quinidine