Modulation of cytochrome P450 3A4 mediated quinine metabolism in healthy volunteers by two honey samples from different floral and geographical sources

Sharon Iyobor Igbinoba, Cyprian Ogbonna Onyeji, Moses Atanda Akanmu


Background: Honey is widely used both for its nutritional and medicinal benefits and reports exist to suggest it may alter the disposition of conventional drugs whose metabolism is mediated by CYP3A4. The study aimed at investigating the effect of multiple dose administration of honey sourced from two different geographical zones in Nigeria, on an antimalarial, quinine and its CYP3A4 mediated metabolism.

Methods: In a randomized cross-over study, twenty healthy volunteers divided into two groups A and B [A used honey (HA) from Northern and B used honey (HB) from Eastern Nigeria; n=10 respectively] received single oral doses of 600 mg quinine sulphate tablet alone  and after 7 days administration of 10 ml of honey (HA or HB)  twice daily. Blood samples collected at the 16th hour following quinine administration were subjected to HPLC analysis.

Results: Compared to baseline, 10 ml of honey HA significantly increased (0.86±0.22 versus 1.36±0.43) (p<0.05; Wilcoxon test); mean metabolic ratio of quinine (3-hydroxyquinine/quinine) in group A subjects. On the other hand, administration of honey HB resulted in a non-significant reduction (p>0.05) (0.84±0.19 versus. 0.69±0.34) of the metabolic ratio of quinine in group B volunteers. Also, the geometric mean [95% CI: 0.63(0.45, 0.91)] of quinine metabolic ratio in the presence of honey HA alone was significantly increased (p=0.02, t-test).

Conclusions: Honey sample from Northern Nigeria significantly stimulated CYP3A4-mediated quinine metabolism as reflected by an increased metabolic ratio of quinine. In conclusion some honey samples may have the potential to significantly modulate CYP3A4 activity, thus honey effects cannot be generalized.


Quinine, Honey, CYP3A4, Metabolic ratio, Drug-food interactions

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Baltrusaityte V, Venskutonis PR, Ceksteryte V. Radical scavenging activity of different floral origin honey and beebread phenolic extracts. Food Chem. 2007;101:502-04.

Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton JW. Interactions of Herbs with Cytochrome P450. Drug Metab Rev. 2003;35:35-8.

Erejuwa OO, Sulaiman SA, Wahab MS. Effects of honey and its mechanisms of action on the development and progression of cancer. Molecules. 2014;19:2497-522.

Ahmed S, Othman NH. Honey as a potential natural anticancer agent: a review of its mechanisms. Evid Based Complement Alternat Med. 2013;2013:829070.

Kassim M, Achoui M, Mustafa MR, Mohd MA, Yusoff KM. Ellagic acid, phenolic acids, and flavonoids in Malaysian honey extracts demonstrate in vitro anti-inflammatory activity. Nutr Res. 2010;30:650-59.

Al-Waili NS, Saloom KY, Al-Waili TN, Al-Waili AN, Akmal M, Al-Waili FS, et al. Influence of various diet regimens on deterioration of hepatic function and hematological parameters following carbon tetrachloride: a potential protective role of natural honey. Nat Prod Res. 2006;20:1258-64.

Chen L, Mechta A, Berebaum M, Zangerl AR, Egeseth NJ. Honeys from different floral sources as inhibitors of enzymatic browning in fruit and vegetable homogenates. J Agric Food Chem. 2000;48:4997-5000.

Gheldof N, Engeseth NJ. Antioxidant capacity of honeys from various floral sources based on the determination of oxygen radical absorbance capacity and inhibition of in vitro lipoprotein oxidation in human serum samples. J Agric Food Chem. 2002;50:3050-5.

Yao L, Jiang Y, D'Arcy B, Singanusong R, Datta N, Caffin N, Raymont K. Quantitative high-performance liquid chromatography analyses of flavonoids in Australian Eucalyptus honeys. J Agric Food Chem. 2004;52:210-4.

Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos. 2003;31:533-9.

Liu DY, Yang M, Zhu HJ, Zheng YF, Zhu XQ. Human pregnane X receptor-mediated transcriptional regulation of cytochrome P450 3A4 by some phytochemicals. Med Sci. 2006;35:8-13.

Viuda-Martos M, Ruiz-Navajas Y, Fernandez-Lopez J, Perez-Alvarez JA. Functional properties of honey, propolis, and royal jelly. J Food Sci. 2008;73:R117-24.

Al-Mamary M, Al-Meeri A, Al-Habori M. Antioxidant activities and total phenolics of different types of honey. Nutri Res 2002;22:1041-47.

Koumaravelou K, Adithan C, Shashindran CH, Asad M, Abraham BK. Effect of honey on carbamazepine kinetics in rabbits. Indian J Exp Biol. 2002;40:560-63.

Koumaravelou K, Adithan C, Shashindran CH, Asad M, Abraham BK. Influence of honey on orally and intravenously administered diltiazem kinetics in rabbits. Indian J Exp Biol. 2002;40:1164-8.

Sukriti J, Garg SK. Influence of honey on the pharmacokinetics of phenytoin in healthy rabbits. Methods Find Exp Clin Pharmacol. 2003;25:367-70.

Tushar T, Vinod T, Rajan S, Shashindran C, Adithan C. Effect of honey on CYP3A, CYP2D6 and CYP2C19 enzyme activity in healthy human volunteers. Basic Clin Pharmacol Toxicol. 2007;100:269-72.

Fetzner L, Burhenne J, Weiss J, Völker M, Unger M, Mikus G, et al. Daily honey consumption does not change CYP3A activity in humans. J Clin Pharmacol. 2011;51:1223-32.

Igbinoba SI, Onyeji CO, Akanmu MA, Soyinka JO, Pullela SS, Cook JM, et al. Effect of dehusked Garcinia kola seed on the overall pharmacokinetics of quinine in healthy human volunteers. J Clin Pharmacol. 2015;55:348-54.

Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144.

Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S. Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine. Br J Clin Pharmacol. 1997;43:245-52.

Wanwimolruk S, Paine MF, Pusek SN, Watkins PB. Is quinine a suitable probe to assess the hepatic drug metabolizing enzyme CYP3A?. Br J Clin Pharmacol. 2002;54:643-51.

Mirghani RA, Ericsson O, Tybring G, Gustafsson LL, Bertilsson L. Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A in man. Eur J Clin Pharmacol. 2003;59:23-8.

Kanebratt KP, Diczfalusy U, Bäckström T, Sparve E, Bredberg E, Böttiger Y, et al. Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4b-hydroxycholesterol. Clin Pharmacol Ther. 2008;84:589-94.

Björkhem-Bergman L, Bäckström T, Nylén H, Rönquist-Nii Y, Bredberg E, Andersson TB, et al. Quinine compared to 4β-hydroxycholesterol and midazolam as markers for CYP3A induction by rifampicin. Drug Metab Pharmacokinet. 2014;29:352-5.

Zhu B, Ou-Yang DS, Cheng ZN, Huang SL, Zhou HH. Single plasma sampling to predict oral clearance of CYP3A probe midazolam. Acta Pharmacol Sin. 2001;22:634-38.

Fujita K. Food-drug interactions via human cytochrome P450 3A (CYP3A). Drug Metab Drug Interact. 2004;20:195-217.

Christensen M, Andersson K, Dale´n P, Mirghani RA, Muirhead GJ, Nordmark A, et al. Pharmacokinetics and drug disposition the karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther. 2003;73:517-28.

Babalola CP, Bolaji OO, Dixon PAF, Ogunbonna FA. Column liquid chromatographic analysis of quinine in human plasma, saliva and urine. J chromatogr. 1993;616:151-4.

Mansell RL, McIntosh CA, Vest SE. An analysis of the limonin and naringin content of grapefruit juice samples collected from Florida state test houses. J Agric Food Chem. 1983;31:156-62.

Salick J, Fangb Z, Byg A. Eastern Himalayan alpine plant ecology, Tibetan ethnobotany, and climate change. Global Environ Chang. 2009;19:147-55.