Effect of Honey on CYP3A4, CYP2D6 and CYP2C19 Enzyme Activity in Healthy Human Volunteers
Tewari Tushar
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorThomas Vinod
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorSundaram Rajan
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorChanolean Shashindran
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorChandrasekaran Adithan
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorTewari Tushar
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorThomas Vinod
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorSundaram Rajan
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorChanolean Shashindran
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorChandrasekaran Adithan
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry, India
Search for more papers by this authorAbstract
Abstract: Honey is a common food supplement but not many studies have studied honey and drug interaction. This study investigates the influence of 7 days of honey administration on the activity of CYP3A4, CYP2D6 and CYP2C19 drug-metabolizing enzymes in healthy volunteers by using appropriate biomarker and probe drugs. A within-group pharmacokinetic study was done in 12 healthy volunteers. Urine samples (0–8 hr) were collected after administration of 30 mg of oral dextromethorphan (probe drug for CYP2D6) for analysis of dextromethorphan and dextrorphan. A plasma sample (4 hr) was collected after administration of 200 mg of oral proguanil (probe drug for CYP2C19) for the analysis of proguanil and cycloguanil. Urine samples (0–24 hr) were collected for the analysis of 6β-hydroxycortisol (biomarker for CYP3A4). The volunteers were administered honey for 7 days. Subsequently blood and urine samples were collected after drug dosing as before. These samples were analysed for drug and metabolite concentrations in urine and plasma using high performance liquid chromatography method. Seven days of honey administration resulted in statistically significant increase in 24-hr urinary excretion of 6β-hydroxycortisol. However, the metabolic ratios of dextromethorphan and proguanil were not significantly altered after 7 days of honey administration. Honey obtained from Western Ghats of southern India may induce CYP3A4 enzyme activity but not CYP2D6 and CYP2C19 enzyme activities.
References
- 1 Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci 2006; 78: 2131–45.
- 2 White JW Jr. Honey. Adv Food Res 1978; 24: 287–374.
- 3 Wrighton SA, VandenBranden M, Ring BJ. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996; 24: 461–73.
- 4 Murray M. Mechanisms and significance of inhibitory drug interactions involving cytochrome P450 enzymes. Int J Mol Med 1999; 3: 227–38.
- 5 Dossing M, Pilsgaard H, Rasmussen B, Poulsen HE. Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism. Eur J Clin Pharmacol 1983; 25: 215–22.
- 6 Bauer S, Stormer E, Kerb R, Johne A, Brockmoller J, Roots I. Differential effects of Saint John's wort (Hypericum perforatum) on the urinary excretion of D-glucaric acid and 6 β-hydroxycortisol in healthy volunteers. Eur J Clin Pharmacol 2002; 58: 581–5.
- 7 Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 1997; 25: 1228–33.
- 8 Liu KH, Kim MJ, Jeon BH et al. Inhibition of human cytochrome P450 isoforms and NADPH-CYP reductase in vitro by 15 herbal medicines, including Epimedii herba. J Clin Pharm Ther 2006; 31: 83–91.
- 9 Markowitz JS, Devane CL, Chavin KD, Taylor RM, Ruan Y, Donovan JL. Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther 2003; 74: 170–7.
- 10 Markowitz JS, Donovan JL, Devane CL et al. Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers. Clin Pharmacol Ther 2003; 74: 536–42.
- 11 Markowitz JS, Donovan JL, Lindsay DeVane C, Sipkes L, Chavin KD. Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J Clin Psychopharmacol 2003; 23: 576–81.
- 12 Donovan JL, DeVane CL, Chavin KD, Taylor RM, Markowitz JS. Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Dispos 2003; 31: 519–22.
- 13 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.
- 14 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: 1164–68.
- 15 Sukriti J, Garg SK. Influence of honey on the pharmacokinetics of phenytoin in healthy rabbits. Methods Find Exp Clin Pharmacol 2003; 25: 367–70.
- 16 Malhotra S, Garg SK, Dixit RK. Effect of concomitantly administered honey on the pharmacokinetics of carbamazepine in healthy volunteers. Methods Find Exp Clin Pharmacol 2003; 25: 537–40.
- 17 Gorski JC, Hall SD, Jones DR, VandenBranden M, Wrighton SA. Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol 1994; 47: 1643–53.
- 18 Schmider J, Brockmoller J, Arold G, Bauer S, Roots I. Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics 1999; 9: 725–34.
- 19 Ged C, Rouillon JM, Pichard L et al. The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol 1989; 28: 373–87.
- 20 Henthorn TK, Benitez J, Avram MJ et al. Assessment of the debrisoquin and dextromethorphan phenotyping tests by gaussian mixture distributions analysis. Clin Pharmacol Ther 1989; 45: 328–33.
- 21 Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 1979; 16: 183–87.
- 22 Lennard MS, Silas JH, Freestone S, Trevethick J. Defective metabolism of metoprolol in poor hydroxylators of debrisoquine. Br J Clin Pharmacol 1982; 14: 301–3.
- 23 Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 1995; 5: 358–63.
- 24 Birkett DJ, Rees D, Andersson T, Gonzalez FJ, Miners JO, Veronese ME. In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. Br J Clin Pharmacol 1994; 37: 413–20.
- 25 Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson GR, Branch RA. Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984; 36: 773–80.
- 26 Homma M, Beckerman K, Hayashi S et al. Liquid chromatographic determination of urinary 6β-hydroxycortisol to assess cytochrome P450 3A activity in HIV positive pregnant women. J Pharm Biomed Anal 2000; 23: 629–735.
- 27 Marshall PS, Straka RJ, Johnson K. Determination of dextromethorphan and its O-demethylated metabolite from urine. Ther Drug Monit 1992; 14: 402–27.
- 28 Setiabudy R, Kusaka M, Chiba K, Darmansjah I, Ishizaki T. Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4′-hydroxylation recruited from an Indonesian population. Br J Clin Pharmacol 1995; 39: 297–303.
- 29 Ho CP, Saville DJ, Wanwimolruk S. Inhibition of human CYP3A4 activity by grape fruit flavanoids, furanocaumarins and related compounds. J Pharm Pharmaceut Sci 2001; 4: 217–27.
- 30 Moore LB, Goodwin B, Jones SA et al. St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000; 97: 7500–2.
- 31 Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 2003; 31: 533–9.
- 32 Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Ther 2002; 96: 67–202.
- 33 Wadelius M, Darj E, Frenne G et al. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther 1997; 62: 400–7.
- 34 Knodell RG, Browne DG, Gwozdz GP, Brian WR, Guengerich FP. Differential inhibition of individual human liver cytochromes P450 by cimetidine. Gastroenterology 1991; 101: 1680–91.
- 35 Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262–5.
- 36 Muralidharan G, Hawes EM, McKay G, Korchinski ED, Midha KK. Quinidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase. Eur J Clin Pharmacol 1991; 41: 471–4.
- 37 Feng HJ, Huang SL, Wang W, Zhou HH. The induction effect of rifampicin on activity of mephenytoin 4′-hydroxylase related to M1 mutation of CYP2C19 and gene dose. Br J Clin Pharmacol 1998; 45: 27–9.
- 38 Svensson US, Ashton M, Trinh NH, Huang SL, Wang W, Zhou HH. Artimisinin induces omeprazole metabolism in human beings. Clin Pharmacol Ther 1998; 64: 160–7.
Citing Literature
