In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6
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Boon Hooi Tan
Abstract
Objectives
Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug–natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6.
Methods
CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6–antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking.
Results
The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro–in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition.
Conclusions
Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.
Funding source: Monash University Malaysia
Award Identifier / Grant number: Seed Grant BCHH-SS-4-02-2010
Funding source: Kementerian Sains, Teknologi dan Inovasi
Award Identifier / Grant number: eScience Fund 02-02-10-SF0077
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Research funding: This work was funded by the Monash University Seed Grant (No. BCHH-SS-4-02-2010) and the eScience Fund (project code 02-02-10-SF0077) of the Malaysian Ministry of Science, Technology and Innovation.
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Author contributions: Boon Hooi Tan and Nafees Ahemad: Sample collection, lab work, analysed data and wrote the manuscript. Chin Eng Ong, Yan Pan, Uma Devi Palanisamy and Iekhsan Othman: Contributed to the development of the study and interpretation of results. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Not applicable.
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Ethical approval: Not applicable.
References
1. Huskisson, EC. Glucosamine and chondroitin for osteoarthritis. J Int Med Res 2008;36:1161–79. https://doi.org/10.1177/147323000803600602.Suche in Google Scholar
2. Gumustas, SA, Yilmaz, İ, Isyar, M, Sirin, DY, Batmaz, AG, Ugras, AA, et al.. Assessing the negative impact of phenyl alkanoic acid derivative, a frequently prescribed drug for the suppression of pain and inflammation, on the differentiation and proliferation of chondrocytes. J Orthop Surg Res 2016;11:70. https://doi.org/10.1186/s13018-016-0406-x.Suche in Google Scholar
3. Bruyère, O. Glucosamine has a disease-modifying effect on osteoarthritis. Menopause 2004;11:138–43. https://doi.org/10.1097/01.gme.0000087983.28957.5d.Suche in Google Scholar
4. Bruyère, O, Altman, RD, Reginster, JY. Efficacy and safety of glucosamine sulfate in the management of osteoarthritis: evidence from real-life setting trials and surveys. Semin Arthritis Rheum 2016;45:S12–7. https://doi.org/10.1016/j.semarthrit.2015.11.011.Suche in Google Scholar
5. Cohen, M, Wolfe, R, Mai, T, Lewis, D. A randomized, double blind, placebo controlled trial of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for osteoarthritis of the knee. J Rheumatol 2003;30:523–8.Suche in Google Scholar
6. Sun, Y, Wang, C, Gong, C. Repairing effects of glucosamine sulfate in combination with etoricoxib on articular cartilages of patients with knee osteoarthritis. J Orthop Surg Res 2020;15:150. https://doi.org/10.1186/s13018-020-01648-z.Suche in Google Scholar
7. Damlar, I, Esen, E, Tatli, U. Effects of glucosamine-chondroitin combination on synovial fluid IL-1beta, IL-6, TNF-alpha and PGE2 levels in internal derangements of temporomandibular joint. Med Oral Patol Oral Cir Bucal 2015;20:e278–83. https://doi.org/10.4317/medoral.20242.Suche in Google Scholar
8. Kahan, A, Uebelhart, D, De Vathaire, F, Delmas, PD, Reginster, JY. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2009;60:524–33. https://doi.org/10.1002/art.24255.Suche in Google Scholar
9. Martel-Pelletier, J, Roubille, C, Abram, F, Hochberg, MC, Dorais, M, Delorme, P, et al.. First-line analysis of the effects of treatment on progression of structural changes in knee osteoarthritis over 24 months: data from the osteoarthritis initiative progression cohort. Ann Rheum Dis 2015;74:547–56. https://doi.org/10.1136/annrheumdis-2013-203906.Suche in Google Scholar
10. Uebelhart, D, Thonar, EJ, Delmas, PD, Chantraine, A, Vignon, E. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthr Cartil 1998;6:39–46. https://doi.org/10.1016/s1063-4584(98)80011-3.Suche in Google Scholar
11. Rovetta, G, Monteforte, P, Molfetta, G, Balestra, V. Chondroitin sulfate in erosive osteoarthritis of the hands. Int J Tissue React 2002;24:29–32.Suche in Google Scholar
12. Fouad, AA, Abdel-Aziz, AM, Hamouda, AAH. Diacerein downregulates NLRP3/caspase-1/IL-1β and IL-6/STAT3 pathways of inflammation and apoptosis in a rat model of cadmium testicular toxicity. Biol Trace Elem Res 2020;195:499–505. https://doi.org/10.1007/s12011-019-01865-6.Suche in Google Scholar PubMed
13. Refaie, MMM, El-Hussieny, M. The role of interleukin-1b and its antagonist (diacerein) in estradiol benzoate-induced endometrial hyperplasia and atypia in female rats. Fundam Clin Pharmacol 2017;31:438–46. https://doi.org/10.1111/fcp.12285.Suche in Google Scholar
14. Steinecker-Frohnwieser, B, Weigl, L, Kullich, W, Lohberger, B. The disease modifying osteoarthritis drug diacerein is able to antagonize pro inflammatory state of chondrocytes under mild mechanical stimuli. Osteoarthr Cartil 2014;22:1044–52. https://doi.org/10.1016/j.joca.2014.05.008.Suche in Google Scholar
15. Fidelix, TS, Macedo, CR, Maxwell, LJ, Trevisani, VFM. Diacerein for osteoarthritis. Cochrane Database Syst Rev 2014;2:CD005117. https://doi.org/10.1002/14651858.CD005117.pub3.Suche in Google Scholar
16. Wienkers, LC, Heath, TG. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 2005;4:825–33. https://doi.org/10.1038/nrd1851.Suche in Google Scholar
17. Pan, Y, Abd-Rashid, BA, Ismail, Z, Ismail, R, Mak, JW, Ong, CE. Heterologous expression of human cytochromes P450 2D6 and CYP3A4 in Escherichia coli and their functional characterization. Protein J 2011;30:581–91. https://doi.org/10.1007/s10930-011-9365-6.Suche in Google Scholar
18. Bendriss, EK, Markoglou, N, Wainer, IW. High-performance liquid chromatography assay for simultaneous determination of dextromethorphan and its main metabolites in urine and in microsomal preparations. J Chromatogr B Biomed Sci Appl 2001;754:209–15. https://doi.org/10.1016/s0378-4347(00)00609-5.Suche in Google Scholar
19. Yao, C, Levy, RH. Inhibition-based metabolic drug–drug interactions: predictions from in vitro data. J Pharmaceut Sci 2002;91:1923–35. https://doi.org/10.1002/jps.10179.Suche in Google Scholar PubMed
20. Dong, AN, Ahemad, N, Pan, Y, Palanisamy, UD, Yiap, BC, Ong, CE. Functional and structural characterisation of common cytochrome P450 2D6 allelic variants-roles of Pro34 and Thr107 in catalysis and inhibition. N Schmied Arch Pharmacol 2019;392:1015–29. https://doi.org/10.1007/s00210-019-01651-0.Suche in Google Scholar PubMed
21. VandenBrink, BM, Foti, RS, Rock, DA, Wienkers, LC, Wahlstrom, JL. Prediction of CYP2D6 drug interactions from in vitro data: evidence for substrate-dependent inhibition. Drug Metab Dispos 2012;40:47–53. https://doi.org/10.1124/dmd.111.041210.Suche in Google Scholar PubMed
22. Nicolas, P, Tod, M, Padoin, C, Petitjean, O. Clinical pharmacokinetics of diacerein. Clin Pharmacokinet 1998;35:347–59. https://doi.org/10.2165/00003088-199835050-00002.Suche in Google Scholar PubMed
23. Hevener, KE, Zhao, W, Ball, DM, Babaoglu, K, Qi, J, White, SW, et al.. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J Chem Inf Model 2009;49:444–60. https://doi.org/10.1021/ci800293n.Suche in Google Scholar
24. Wang, A, Savas, U, Hsu, MH, Stout, CD, Johnson, EF. Crystal structure of human cytochrome P450 2D6 with prinomastat bound. J Biol Chem 2012;287:10834–43. https://doi.org/10.1074/jbc.m111.307918.Suche in Google Scholar
25. McLaughlin, LA, Paine, MJ, Kemp, CA, Maréchal, JD, Flanagan, JU, Ward, CJ, et al.. Why is quinidine an inhibitor of cytochrome P450 2D6? The role of key active-site residues in quinidine binding. J Biol Chem 2005;280:38617–24. https://doi.org/10.1074/jbc.m505974200.Suche in Google Scholar
26. Paine, MJ, McLaughlin, LA, Flanagan, JU, Kemp, CA, Sutcliffe, MJ, Roberts, GC, et al.. Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regioselectivity in cytochrome P450 2D6. J Biol Chem 2003;278:4021–7. https://doi.org/10.1074/jbc.m209519200.Suche in Google Scholar
27. Lee, KS, Kim, SK. Direct and metabolism-dependent cytochrome P450 inhibition assays for evaluating drug–drug interactions. J Appl Toxicol 2013;33:100–8. https://doi.org/10.1002/jat.1720.Suche in Google Scholar
28. Broly, F, Libersa, C, Lhermitte, M, Bechtel, P, Dupuis, B. Effect of quinidine on the dextromethorphan O-demethylase activity of microsomal fractions from human liver. Br J Clin Pharmacol 1989;28:29–36. https://doi.org/10.1111/j.1365-2125.1989.tb03502.x.Suche in Google Scholar
29. Ching, MS, Blake, CL, Ghabrial, H, Ellis, SW, Lennard, MS, Tucker, GT, et al.. Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites. Biochem Pharmacol 1995;50:833–7. https://doi.org/10.1016/0006-2952(95)00207-g.Suche in Google Scholar
30. Matsunaga, M, Yamazaki, H, Kiyotani, K, Iwano, S, Saruwatari, J, Nakagawa, K, et al.. Two novel CYP2D6*10 haplotypes as possible causes of a poor metabolic phenotype in Japanese. Drug Metab Dispos 2009;37:699–701. https://doi.org/10.1124/dmd.108.026096.Suche in Google Scholar PubMed
31. Misaka, S, Kawabe, K, Onoue, S, Werba, JP, Giroli, M, Tamaki, S, et al.. Effects of green tea catechins on cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A activities in human liver and intestinal microsomes. Drug Metabol Pharmacokinet 2013;28:244–9. https://doi.org/10.2133/dmpk.dmpk-12-rg-101.Suche in Google Scholar PubMed
32. Shen, H, He, MM, Liu, H, Wrighton, SA, Wang, L, Guo, B, et al.. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos 2007;35:1292–300. https://doi.org/10.1124/dmd.107.015354.Suche in Google Scholar PubMed
33. Guengerich, FP, Miller, GP, Hanna, IH, Sato, H, Martin, MV. Oxidation of methoxyphenethylamines by cytochrome P450 2D6. Analysis of rate-limiting steps. J Biol Chem 2002;277:33711–9. https://doi.org/10.1074/jbc.m205146200.Suche in Google Scholar
34. Maréchal, JD, Kemp, CA, Roberts, GC, Paine, MJ, Wolf, CR, Sutcliffe, MJ. Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6-drug interactions. Br J Pharmacol 2008;153:S82–9. https://doi.org/10.1038/sj.bjp.0707570.Suche in Google Scholar PubMed PubMed Central
35. Persiani, S, Rotini, R, Trisolino, G, Rovati, LC, Locatelli, M, Paganini, D, et al.. Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose. Osteoarthr Cartil 2007;15:764–72. https://doi.org/10.1016/j.joca.2007.01.019.Suche in Google Scholar PubMed
36. Persiani, S, Canciani, L, Larger, P, Rotini, R, Trisolino, G, Antonioli, D, et al.. In vitro study of the inhibition and induction of human cytochromes P450 by crystalline glucosamine sulfate. Drug Metabol Drug Interact 2009;24:195–209. https://doi.org/10.1515/dmdi.2009.24.2-4.195.Suche in Google Scholar PubMed
37. Rowland, P, Blaney, FE, Smyth, MG, Jones, JJ, Leydon, VR, Oxbrow, AK, et al.. Crystal structure of human cytochrome P450 2D6. J Biol Chem 2006;281:7614–22. https://doi.org/10.1074/jbc.m511232200.Suche in Google Scholar PubMed
38. Tang, JC, Yang, H, Song, XY, Song, XH, Yan, SL, Shao, JQ, et al.. Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes. Phytother Res 2009;23:159–64. https://doi.org/10.1002/ptr.2572.Suche in Google Scholar PubMed
39. Kumar, V, Rock, DA, Warren, CJ, Tracy, TS, Wahlstrom, JL. Enzyme source effects on CYP2C9 kinetics and inhibition. Drug Metab Dispos 2006;34:1903–8. https://doi.org/10.1124/dmd.106.010249.Suche in Google Scholar PubMed PubMed Central
40. Yu, A, Dong, H, Lang, D, Haining, RL. Characterization of dextromethorphan O- and N-demethylation catalyzed by highly purified recombinant human CYP2D6. Drug Metab Dispos 2001;29:1362–5.Suche in Google Scholar
41. Armani, S, Ting, L, Sauter, N, Darstein, C, Tripathi, AP, Wang, L, et al.. Drug interaction potential of osilodrostat (LCI699) based on its effect on the pharmacokinetics of probe drugs of cytochrome P450 enzymes in healthy adults. Clin Drug Invest 2017;37:465–72. https://doi.org/10.1007/s40261-017-0497-0.Suche in Google Scholar PubMed PubMed Central
42. Siu, YA, Hao, MH, Dixit, V, Lai, WG. Celecoxib is a substrate of CYP2D6: impact on celecoxib metabolism in individuals with CYP2C9*3 variants. Drug Metabol Pharmacokinet 2018;33:219–27. https://doi.org/10.1016/j.dmpk.2018.06.001.Suche in Google Scholar PubMed
© 2021 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Review
- Oxy+ (arthrospira) and its medicinal importance: an appraisal
- Original Articles
- In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6
- Efficacy of Majoon-e-Seer Alvi Khan in dyslipidemia: a single blind randomized standard controlled clinical trial
- Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy
- Evaluation of the need for pharmacogenomics testing among physicians in the West Bank of Palestine
- Habitual khat chewing alters urinary inorganic profile in adult healthy males
- Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone
- Ocimum gratissimum leaf extract ameliorates phenylhydrazine-induced anaemia and toxicity in Wistar rats
- Lactobacillus plantarum mitigates sexual-reproductive deficits by modulating insulin receptor expression in the hypothalamic-pituitary-testicular axis of hyperinsulinemic mice
- Consumption of Ashtanga Ghrita (clarified cow butter added with herb extracts) improves cognitive dysfunction induced by scopolamine in rats via regulation of acetylcholinesterase activity and oxidative stress
- Letter to the Editor
- Fatal thiopurine toxicity: pre-emptive testing of NUDT15 415C>T polymorphism may be life saving in South Asian population
Artikel in diesem Heft
- Frontmatter
- Review
- Oxy+ (arthrospira) and its medicinal importance: an appraisal
- Original Articles
- In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6
- Efficacy of Majoon-e-Seer Alvi Khan in dyslipidemia: a single blind randomized standard controlled clinical trial
- Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy
- Evaluation of the need for pharmacogenomics testing among physicians in the West Bank of Palestine
- Habitual khat chewing alters urinary inorganic profile in adult healthy males
- Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone
- Ocimum gratissimum leaf extract ameliorates phenylhydrazine-induced anaemia and toxicity in Wistar rats
- Lactobacillus plantarum mitigates sexual-reproductive deficits by modulating insulin receptor expression in the hypothalamic-pituitary-testicular axis of hyperinsulinemic mice
- Consumption of Ashtanga Ghrita (clarified cow butter added with herb extracts) improves cognitive dysfunction induced by scopolamine in rats via regulation of acetylcholinesterase activity and oxidative stress
- Letter to the Editor
- Fatal thiopurine toxicity: pre-emptive testing of NUDT15 415C>T polymorphism may be life saving in South Asian population
