Evaluation of metabolism and cytochrome P450 mediated interaction liabilities of naringenin


Submitted: 11 February 2023
Accepted: 21 March 2023
Published: 13 April 2023
Abstract Views: 1907
PDF: 171
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Naringenin is one of the major components of grapefruit juice. It has a broad spectrum of pharmacological activities, and many studies report that grapefruit juice inhibits cytochrome P450 (CYP) 3A4 leading to drug interactions. Naringenin was profiled through various in vitro studies like metabolic stability and glucuronidation in rat and human liver microsomes while, CYP inhibition using human liver microsomes. In addition, pharmacokinetic profiling was conducted upon intravenous (i.v.) and oral administration in rats. Naringenin undergoes both phase I and phase II metabolism in rat liver microsomes, and in human liver microsomes, it is predominantly metabolized by phase II. Glucuronidation which is addition (conjugation) of glucuronic acid to various functional groups is one of the major metabolic pathways of Naringenin. Naringenin, at 1.0 μM and 10.0 μM, did not elicit any appreciable inhibition of the 5 major CYP isoforms (CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6). Oral pharmacokinetic studies at 100, 300,and 1000 mg/kg dose and intravenous pharmacokinetic studies at 1 mg/kg dose were performed in male SD rats. Naringenin exhibited very short half-life (0.27 h) and rapid elimination (Clearance=110.65 mL/min/kg) after i.v. administration. There was saturation in Cmax and exposure beyond 100 mg/kg, and the absolute bioavailability was found to be ≤ 5% at the tested oral doses. This present experiment suggests that naringenin does not substantially inhibit CYP3A4 (or any of the tested five isoforms) isoforms per se. Given the minimal involvement of CYP enzymes in the metabolism of naringenin and minimal inhibition of CYP enzymes (IC50> 10 μM), the potential for drug-drug interactions involving CYP substrates and inhibitors is very minimal in humans.


Zhoupeng Z, Wei T. Drug metabolism in drug discovery and development. Acta Pharm Sin B 2018;8:721–732. DOI: https://doi.org/10.1016/j.apsb.2018.04.003

Guidance for Industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.

Fellers PJ, Nikdel S, Lee HS. Nutrient content and nutrition labeling of several processed Florida citrus juice products. J Am Diet Assoc 1990;90:1079–84. DOI: https://doi.org/10.1016/S0002-8223(21)01704-1

Lee YS, Lorenz BJ, Koufis T, Reidenberg MM. Grapefruit juice and its flavonoids inhibit 11 beta-hydroxysteroid dehydrogenase. Clin Pharmacol Ther 1996;59:62-71. DOI: https://doi.org/10.1016/S0009-9236(96)90025-9

Patel K, Singh GK, Patel DK. A review on pharmacological and analytical aspects of naringenin. Chin J Integr Med 2018;24:551-60. DOI: https://doi.org/10.1007/s11655-014-1960-x

Rani N, Bharti S, Krishnamurthy B, et al. Pharmacological properties and therapeutic potential of naringenin: a citrus flavonoid of pharmaceutical promise. Curr Pharm Des 2016;22:4341-59.

Nouri Z, Fakhri S, El-Senduny FF, Sanadgol N, et al. On the neuroprotective effects of naringenin: pharmacological targets, signaling pathways, molecular mechanisms, and clinical perspective. Biomolecules 2019;9:690. DOI: https://doi.org/10.3390/biom9110690

Kurowska EM, Borradaile NM, Spence JD, Carroll KK. Hypocholesterolemic effects of dietary citrus juices in rabbits. Nutr Res 2000;20:121–9. DOI: https://doi.org/10.1016/S0271-5317(99)00144-X

Goldwasser J, Cohen PY, Yang E, et al. Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: Role of PPARα, PPARγ and LXRα. PLoS One 2010;5. DOI: https://doi.org/10.1371/journal.pone.0012399

Mulvihill EE, Allister EM, Sutherland BG, et al. Naringenin prevents dyslipidemia, apoB overproduction and hyperinsulinemia in LDL-receptor null mice with diet-induced insulin resistance. Diabetes 2009;58:2198-210. DOI: https://doi.org/10.2337/db09-0634

Lee CH, Jeong TS, Choi YK, et al. Anti-atherogenic effect of citrus flavonoids, naringin and Naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem Biophys Res Commun 2001;284:681–8. DOI: https://doi.org/10.1006/bbrc.2001.5001

Wilcox LJ, Borradaile NM, Huff MW. Antiatherogenic properties of naringenin, a citrus flavonoid. Cardiovasc Drug Rev 1999;17:160–78. DOI: https://doi.org/10.1111/j.1527-3466.1999.tb00011.x

Frydoonfar HR, McGrath DR, Spigelman AD. The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid naringenin. Colorectal Dis 2003;5:149-52. DOI: https://doi.org/10.1046/j.1463-1318.2003.00444.x

Harmon AW, Patel YM. Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation. Breast Cancer Res Treat 2004;85:103-10. DOI: https://doi.org/10.1023/B:BREA.0000025397.56192.e2

Cushnie TP, Lamb AJ. Antimicrobial activity of flavonoids. Int J Antimicrob Agents 2005;26:343-56. DOI: https://doi.org/10.1016/j.ijantimicag.2005.09.002

Chen YT, Zheng RL, Jia ZJ, Ju Y. Flavonoids as superoxide scavengers and antioxidants. Free Radic Biol Med 1990;9:19-21. DOI: https://doi.org/10.1016/0891-5849(90)90045-K

Lakshmi V, Joseph SK, Srivatsava S, et al. Antifilarial activity in vitro and in vivo of some flavonoids tested against brugiamalayi. Acta Trop 2010;116:127-33. DOI: https://doi.org/10.1016/j.actatropica.2010.06.006

Arthur YK. A Pilot study of the grapefruit flavonoid naringenin for HCV Infection. Massachusetts General Hospital. Harvard University, 2010, NCT01091077.

Nahmias Y, Goldwasser J, Casali M, et al. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology 2008;47:1437–45. DOI: https://doi.org/10.1002/hep.22197

Heo HJ, Kim MJ, Lee JM, et al. Naringenin from citrus junos has an inhibitory effect on acetylcholinesterse (Ache) and a mitigating effect on amnesia. Dement Geriatr Cogn Disord 2004;17:151-7. DOI: https://doi.org/10.1159/000076349

Badary OA, Abdel MS, Ahmed WA, Owieda GH. Naringenin attenuates cisplatin nephrotoxicity in rats. Life Sci 2005;76:2125-35. DOI: https://doi.org/10.1016/j.lfs.2004.11.005

Du G, Jin L, Han X, et al. Naringenin: A potential immunomodulator for inhibiting lung fibrosis and metastasis. Cancer Res 2009;69:3205–12. DOI: https://doi.org/10.1158/0008-5472.CAN-08-3393

Chia LC, Ching SW, Nen CC, et al. Naringenin more effectively inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in macrophages than in microglia. Nutr Res 2010;30:858-64. DOI: https://doi.org/10.1016/j.nutres.2010.10.011

Neha R, Saurabh B, Bhaskar K, et al. Pharmacological properties and therapeutic potential of naringenin: A citrus flavonoid of pharmaceutical promise. Curr Pharm Design 2016;22:4341-59. DOI: https://doi.org/10.2174/1381612822666160530150936

Venkateswara RP, Kiran SVDS, Rohini P, Bhagyasree P. Flavonoid: A review on naringenin. J Pharmacogn Phytochem 2017;6:2778-83.

Fuhr U, Klittich K, Staib AH. Inhibitory effect of grapefruit juice and its bitter principal, Naringenin, on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol 1993;35:431-6. DOI: https://doi.org/10.1111/j.1365-2125.1993.tb04162.x

Kane GC, Lipsky JJ. Drug-Grapefruit interactions. Mayo Clin Proc 2000;75:933-942.

Mariana CS, Rodolpho CB, Bertilha ASC, et al. In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9. Food Res Int 2013;50:102-10. DOI: https://doi.org/10.1016/j.foodres.2012.09.027

Lin H, Kent UM, Hollenberg PF. The grapefruit juice effect is not limited to cytochrome P450(P450) 3A4: Evidence for bergamotten-dependent inactivation, heme destruction, and covalent binding to protein in P450s 2B6 and 3A5. J. Pharmacol Exp Ther 2005;313:154-64. DOI: https://doi.org/10.1124/jpet.104.079608

Cohen LH, Remley MJ, Raunig D, Vaz ADN. In vitro drug interactions of cytochrome p450: an evaluation of fluorogenic to conventional substrates. Drug Metab Dispos 2003;31:1005–15. DOI: https://doi.org/10.1124/dmd.31.8.1005

Mertens TSU, Zadezensky WV, De Castro WV, et al. Grapefruit-drug interactions: Can interactions with drugs be avoided? J Clin Pharmacol 2006;46:1390-1416. DOI: https://doi.org/10.1177/0091270006294277

Bailey D, Spence J, Munoz C, Arnold JMO. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991;337:268-9. DOI: https://doi.org/10.1016/0140-6736(91)90872-M

Jawad K, Sardar ZI. Medicinal importance of grapefruit juice and its interaction with various drugs. Nutr J 2007;6:33-42. DOI: https://doi.org/10.1186/1475-2891-6-33

Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug interaction. Br J Clin Pharmacol 1998;46:101–10. DOI: https://doi.org/10.1046/j.1365-2125.1998.00764.x

Miniscalco A, Lundahl J, Regardh CG, et al. Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice. J Pharmacol Exp Ther 1992;261:1195-9.

Ping CH, Dorothy JS, Sompon W. Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J Pharm Pharmaceut Sci 2001;4:217-27.

Le Goff-Klein N, Klein L, Herin M, et al. Inhibition of in-vitro simvastatin metabolism in rat liver microsomes by bergamottin, a component of grapefruit juice. J Pharm Pharmacol 2004;56:1007–14. DOI: https://doi.org/10.1211/0022357044012

Janet MN. Grapefruit juice interactions. Aust Prescr 2002;2537.

Garvan C, Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000;75:933-42. DOI: https://doi.org/10.4065/75.9.933

Interactions with grapefruit juice. Aust Adverse Drug React Bull 2002;21:14. DOI: https://doi.org/10.1007/BF03256201

Pingili RB, Vemulapalli S, Dirisala VR, et al. Effect of naringenin on the pharmacokinetics of metoprolol succinate in rats. Xenobiotica 2021;51:926-32.

Wang B, Shen J, Zhou Q, et al. Effects of naringenin on the pharmacokinetics of tofacitinib in rats. Pharm Biol 2020;58:225-30. DOI: https://doi.org/10.1080/13880209.2020.1738504

Seol HC, Choi JS, et al. Pharmacokinetic interaction between diltiazem and naringenin in rabbits. Korean J Clin Pharm 2006;16:57-62.

Pingili RB, Vemulapalli S, Dirisala VR, et al. Effect of naringenin on the pharmacokinetics of metoprolol succinate in rats. Xenobiotica 2021;51:926-32. DOI: https://doi.org/10.1080/00498254.2021.1942311

Salehi B, Fokou PVT, Sharifi-Rad M, et al. The Therapeutic Potential of Naringenin: A Review of Clinical Trials. Pharmaceuticals (Basel) 2019;12:11. DOI: https://doi.org/10.3390/ph12010011

Samarla, M., & Sangana, R. R. (2023). Evaluation of metabolism and cytochrome P450 mediated interaction liabilities of naringenin. Pre-Clinical Research, 1(1). https://doi.org/10.4081/pcr.2023.9686

Downloads

Download data is not yet available.

Citations