Effect of Vernonia Amygdalina Leaf on Cytochrome P450 2D6- and 3A4-Mediated Metabolism of Dextromethorphan in Healthy Nigerian Subjects

Main Article Content

Mariam Olaide Oladepo
Adebanjo Jonathan Adegbola
Julius Olugbenga Soyinka
Cyprian Ogbona Onyeji

Abstract

Back-ground and Objectives: The study’s focus is to investigate the effects of Vernonia amygdalina on the metabolic activities of Cytochrome P450 3A4 and 2D6 in vivo. The assessment was based on CYP2D6-mediated O-demethylation and CYP3A4-mediated N-demethylation of dextromethorphan (DEX) to Dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively.

Methods: The clinical study followed a two-phase cross over study with two weeks washout period. Volunteers received a single oral dose of DEX 30 mg alone in phase 1 and along with last dose of V. amygdalina leaf powder in phase 2. 8-hour urine samples were collected in both phases post-administration of DEX and analyzed using HPLC-UV. The chromatographic separation of DEX, DOR, 3-MM, and Imatinib was achieved on a C18 column. The analytes were eluted with a gradient elution consisting of 50mM potassium dihydrogen phosphate (pH 5)-acetonitrile at a 1 mL/min flow rate, and detected at 280 nm. Activities of the enzymes investigated were evaluated using the urinary metabolic ratios of DEX:DOR and DEX:3-MM.

Results: Median (interquartile range) values for the metabolic ratios of DEX:DOR was 0.032 (0.028-0.246) and 0.029 (0.018-0.061) for phases with and without V. amygdalina respectively, while the average median values for DEX:3MM was 5.087 (3.692-71.420) and 5.609 (3.093-19.197) for phases with and without V. amygdalina respectively. However, the differences between both phases were not significant for both isoenzymes.

Conclusion: V. amygdalina does not significantly affect the activities of CYP2D6 and CYP3A4 In vivo, which indicates that it has minimal potential to interact with the substrates of both isoenzymes.

Keywords:
Vernonia amygdalina, cytochrome P450 2D6, cytochrome P450 3A4, dextromethorphan

Article Details

How to Cite
Oladepo, M. O., Adegbola, A. J., Soyinka, J. O., & Onyeji, C. O. (2021). Effect of Vernonia Amygdalina Leaf on Cytochrome P450 2D6- and 3A4-Mediated Metabolism of Dextromethorphan in Healthy Nigerian Subjects. Journal of Advances in Medical and Pharmaceutical Sciences, 23(2), 22-32. https://doi.org/10.9734/jamps/2021/v23i230220
Section
Original Research Article

References

WHO. WHO Medicine Strategy. 2002-2005. World Health Organization; 2002.

Cascorbi I. Drug Interactions. Deutsches Aerzteblatt Online. 2012;109:33-34.
DOI: 10.3238/arztebl.2012.0546

Bachmann K. Chapter 8 - Drug Metabolism. Published online 2009:43.

Leucuta S, Vlase L. Pharmacokinetics and metabolic drug interactions. Current Clinical Pharmacology. 2006;1(1):5-20.
DOI: 10.2174/157488406775268183

Lynch T, Price A. The effect of cytochrome p450 metabolism on drug response, interactions, and adverse effects. American Family Physician. 2007;76(3): 391-396.

Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352(21): 2211-2221.

Guengerich FP, Munro AW. Unusual cytochrome P450 enzymes and reactions. J Biol Chem. 2013;288(24):17065-17073.

Zhou S-F. Polymorphism of human cytochrome P450 2D6 and its clinical significance. Clin Pharmacokinet. 2009; 48(11):689-723.

Ogunbona FA, Cyprian O. Onyeji, Oluseye O. Bolaji, Adedayo Adedoyin. Pharmacokinetics: Principles and Application. 1st ed. Ibadan University Press; 2014.

Yu A, Haining RL. Comparative contribution to dextromethorphan metabolism by cytochrome P450 isofroms invitro: Can dextromethorphan be used as a dual probe for both CYP2D6 and CYP3A4 activities?. Drug Metabolism and Disposition. 2001;29(11):1514-1520.

Tushar T, Vinod T, Rajan S, Shashindran C, Adithan C. Effect of Honey on CYP3A4, CYP2D6 and CYP2C19 Enzyme Activity in Healthy Human Volunteers. Basic & Clinical Pharmacology & Toxicology. 2007; 100(4):269-272.

Al-Jenoobi FI, Al-Thukair AA, Alam MA, et al. Effect of Curcuma longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects. Eur J Drug Metab Pharmacokinet. 2015; 40(1):61-66.

Al-Jenoobi FI, Al-Thukair AA, Alam MA, et al. Modulation of CYP2D6 and CYP3A4 metabolic activities by Ferula asafetida resin. Saudi Pharmaceutical Journal. 2014;22(6):564-569.

Al-Jenoobi FI, Al-Thukair AA, Alam MA, et al. Effect of Trigonella foenum-graecum L. on Metabolic Activity of CYP2D6 and CYP3A4. Complement Med Res. 2015; 22(3):180-184.

Al-Jenoobi F, Al-Thukair A, Abbas F, et al. Effect of Black Seed on Dextromethorphan O- and N-Demethylation in Human Liver Microsomes and Healthy Human Subjects. Drug Metabolism Letters. 2010;4(1):51-55.

Chung H, Yang W, Choi H, Jin W, Sihn S, Yoo Y. Pharmacokinetic study of dextromethorphan with urinary excretion. Problems of Forensic Sciences. 2000;43: 57-61.

Schmider JR, Greenblatt DJ, Fogelman SM, Moltke LLV, Shader RI. Metabolism of Dextromethorphan in vitro: Involvement of Cytochromes P450 2D6 and 3A3/4, with a Possible Role of 2E1. Biopharmaceutics & drug disposition. 1997;18(3):227-240.

Gorski JC, Jones DR, Wrighton SA, Hall SD. Characterization of dextromethorphan N-demethylation by human liver microsomes. Biochemical Pharmacology. 1994;48(1):173-182.

Kuo BP-C, Hu OY-P, Hsiong C-H, Pao L-H, Chen T-S, Hung C-F. Single-point plasma or urine dextromethorphan method for determining CYP3A activity. Biopharm Drug Dispos. 2003;24(9):367-373.

Rodrigues AD, ed. Drug-Drug Interactions. Informa healthcare. 2008;179.

Yeh G-C, Tao P-L, Ho H-O, Lee Y-J, Chen JY-R, Sheu M-T. Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes. Journal of Biomedical Science. 2003;10(5):552-564.

Wojtczak A, Rychlik-Sych M, Krochmalska-Ulacha E, Skrêtkowicz J. CYP2D6 phenotyping with dextromethorphan. Pharmacological Reports. 2007;50:734-738.

Usia T, Iwata H, Hiratsuka A, Watabe T, Kadota S, Tezuka Y. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants. Phytomedicine. 2006; 13(1-2):67-73.

Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and P-glycoprotein. Life Sciences. 2002;71(10):1149-1160.

Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice–drug interactions. British Journal of Clinical Pharmacology. 1998;46:10.

Bedada W, de Andrés F, Engidawork E, et al. The psychostimulant khat (Catha edulis) inhibits CYP2D6 enzyme activity in humans. Journal of Clinical Psychopharmacology. 2015;35(6):694-699.

Bedada W, de Andrés F, Engidawork E, Hussein J, LLerena A, Aklillu E. Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations. Sci Rep. 2018;8(12726):1.

Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St John’s Wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. 2003;290(11):5.

Mannel DM. St. John’s wort drug interactions – review of mechanisms and clinical implications. Published online 2004;55.

Farombi EO, Owoeye O. Antioxidative and Chemopreventive Properties of Vernonia amygdalina and Garcinia biflavonoid. International Journal of Environmental Research and Public Health. 2011;8(6):2533-2555.

Alara OR, Abdurahman NH, Ukaegbu CI, Kabbashi NA. Extraction and characterization of bioactive compounds in Vernonia amygdalina leaf ethanolic extract comparing Soxhlet and microwave-assisted extraction techniques. Journal of Taibah University for Science. 2019; 13(1):414-422.

Oladosu-Aayi R, Dienye H, Ajayi C, Erinle O. Comparative Screening of Phytochemical Compounds in Scent Leaf (Ocimum gratissimum) and Bitter Leaf (Vernonia amygdalina) Extracts. J Fisheries Livest Prod. 2017;5(3):242.

Audu SA, Taiwo AE, Ojuolape AR, Sani AS, Bukola AR, Mohammed I. A Study Review of Documented Phytochemistry of Vernonia amygdalina (Family Asteraceae) as the Basis for Pharmacologic Activity of Plant Extract. Journal of Natural Sciences Research. 2012;2(7).

Imaga NOA, Bamigbetan DO. In vivo biochemical assessment of aqueous extracts of Vernonia amygdalina (Bitter leaf). International Journal of Nutrition and Metabolism. 2013;5(2):22-27.

Alara OR, Abdurahman NH, Mudalip SKA, Olalere OA. Phytochemical and pharmacological properties of Vernonia Amygdalina: A review. Journal of Chemical Engineering and Industrial Biotechnology. 2017;2:80-96.

Challand S, Willcox M. A Clinical Trial of the Traditional Medicine Vernonia amygdalina in the Treatment of Uncomplicated Malaria. The Journal of Alternative and Complementary Medicine. 2009;15(11):1231-1237.

Egedigwe CA, Ijeh II, Okafor PN, Ejike CECC. Aqueous and methanol extracts of Vernonia amygdalina leaves exert their anti-obesity effects through the modulation of appetite-regulatory hormones. Pharmaceutical Biology. 2016;54(12): 3232-3236.

Egharevba C. Significance of Bitter Leaf (Vernonia Amagdalina) in tropical diseases and beyond: A review. Malaria Chemotherapy Control and Elimination. 2014;3(120).

Oboh FOJ, Masodje HI. Nutritional and antimicrobial properties of Vernonia amygdalina Leaves. International Journal of Biomedical and Health Sciences. 2009;5(2).

Oyeyemi IT, Akinlabi AA, Adewumi A, Aleshinloye AO, Oyeyemi OT. Vernonia amygdalina : A folkloric herb with anthelminthic properties. Beni-Suef University Journal of Basic and Applied Sciences. 2018;7(1):43-49.

Shewo BS, Girma B. Review on nutritional and medicinal values of Vernonia amygdalina and its uses in human and veterinary medicines. Global Veterinaria. 2017;19(3):562-568.

Wahyudi W, Suwarso E, Nainggolan M. Anti-ulcer activity of african leaves (vernonia amygdalina del.) ethanol extract on male rat. Asian Journal of Pharmaceutical and Clinical Research. 2018;11(3):375-378.

Achuba FI. Role of bitter leaf (Vernonia amygdalina ) extract in prevention of renal toxicity induced by crude petroleum contaminated diets in rats. International Journal of Veterinary Science and Medicine. 2018;6(2):172-177.

Owolabi MA, Adeniji EA, Oribayo OO, Akindehin OE. Effects of Vernonia amygdalina Aqueous Leaf Extract on the Pharmacokinetics of Nifedipine in Rabbits. Journal of Pharmacognosy and Phytochemistry. 2013;2(1):55-65.

Olorunfemi EA, Arnold IC, Chinenye I, Adaora I, Johnson E, Barido D. Effects of the leaf extract of Vernonia amygdalina on the pharmacokinetics of Dihydroartemisinin in Rat. Pharmacologia. 2012;3(12):713-718.

Hassan HS, Odunola MT, Garba M, Usman MA. Effect of vernonia amygdalina leaves on the pharmacokinetics of chlorpropamide in man. Nigerian Journal of Pharmaceutical Sciences. 2007;6(2):34-39.

Al-Jenoobi FI, Al-Thukair AA, Alam MA, et al. Effect of Garden Cress Seeds Powder and Its Alcoholic Extract on the Metabolic Activity of CYP2D6 and CYP3A4. Evidence-Based Complementary and Alternative Medicine. 2014;2014:1-6.

Daali Y, Cherkaoui S, Doffey-Lazeyras F, Dayer P, Desmeules JA. Development and validation of a chemical hydrolysis method for dextromethorphan and dextrophan determination in urine samples: Application to the assessment of CYP2D6 activity in fibromyalgia patients. Journal of Chromatography B. 2008;861(1):56-63.

British Pharmacopoeia Commission. British Pharmacopoeia. The Stationery Office; 2008.

Jones DR, Gorski JC, Haehner DB, O’mara ME, Hall SD. Detemination of cytochrome P450 3A4/5 activity in vivo with dextromethorphan N- demethylation. Clinical Pharmacology Theray. 1996;60(4): 374-378.

Kawashima Y, Hagiwara M, Inoue Y, Someya T. Evaluation of Dextromethorphan N-Demethylation Activity as a Biomarker for Cytochrome P450 3A Activity in Man. Pharmacology and Toxicology. 2002;90(2):82-88.

Bogaards JJP, Bertrand M, Jackson P, et al. Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica. 2000;30(12):1131-1152.

DOI: 10.1080/00498250010021684

Cho H-J, Yoon I-S. Pharmacokinetic interactions of herbs with cytochrome P450 and P-Glycoprotein. Evidence-Based Complementary and Alternative Medicine. 2015;2015:1-10.

Wu X, Ma J, Ye Y, Lin G. Transporter modulation by Chinese herbal medicines and its mediated pharmacokinetic herb–drug interactions. Journal of Chromatography B. 2016;1026:236-253.

Stieger B, Mahdi ZM, Jäger W. Intestinal and Hepatocellular Transporters: Therapeutic Effects and Drug Interactions of Herbal Supplements. Annu Rev Pharmacol Toxicol. 2017;57:13.1-13.18.

Oga EF, Sekine S, Shitara Y, Horie T. Pharmacokinetic Herb-Drug Interactions: Insight into Mechanisms and Consequences. European Journal of Drug Metabolism and Pharmacokinetics. 2016; 41(2):93-108.

Lin C-C, Fan H-Y, Kuo C-W, Pao L-H. Evaluation of Chinese-Herbal-Medicine-Induced Herb-Drug Interactions: Focusing on Organic Anion Transporter. Evidence-Based Complementary and Alternative Medicine. 2012;2012:12.

Onyeji CO, Igbinoba SI, Olayiwola G, Adehin A. Insight into clinically effective herbal antimalarial products: Effects on drug metabolizing enzymes and p-glycoprotein. :23.

Mayr S, Buchner A, Erdfelder E, Faul F. A short tutorial of GPower. Tutorials in Quantitative Methods for Psychology. 2007;3(2):51-59.

Perugini M, Gallucci M, Costantini G. A practical primer to power analysis for simple experimental designs. International Review of Social Psychology. 2018; 31(1):1-23.

Kamimori GH, Karyekar CS, Otterstetter R, et al. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. International Journal of Pharmaceutics. 2002;234(1-2):159-167.

Loftsson T. Introduction. In: Essential Pharmacokinetics. Elsevier. 2015;1-8.