Turkiye Klinikleri Journal of Veterinary Sciences

.: REVIEW
Vitaminler ile İlaçlar Arasındaki Etkileşim
Interaction Between Vitamins and Drugs
Zeynep ÖZDEMİR KÜTAHYAa, Bünyamin TRAŞb
aÇukurova Üniversitesi Ceyhan Veteriner Fakültesi, Farmakoloji ve Toksikoloji ABD, Adana, TÜRKİYE
bSelçuk Üniversitesi Veteriner Fakültesi, Farmakoloji ve Toksikoloji ABD, Konya, TÜRKİYE
Turkiye Klinikleri J Vet Sci. 2021;12(2):79-91
doi: 10.5336/vetsci.2020-79060
Article Language: TR
Full Text
ÖZET
 Canlı vücudunda tamamı sentezlenemeyen vitaminler, fizyolojik fonksiyonlar için gerekli olup kendilerine özgü spesifik görevleri olan maddelerdir. İlaç-ilaç ve ilaç-gıda etkileşimleri, ilaçların istenmeyen etkilerinin ortaya çıkmasında büyük rol oynar. Farmakokinetik temelli ilaç etkileşimleri daha çok enzim ve taşıyıcı transmembran proteinler düzeyinde gözlenir. Metabolik reaksiyonların çoğu sitokrom P450 ailesi tarafından gerçekleştirilir. Enzim aktivitesinin, inhibisyonu veya indüksiyonu substrat ilacın konsantrasyonunu değiştirir. ATP-bağlayıcı kaset taşıyıcılarından, Pglikoprotein ve meme kanser direnç proteini toksik maddelerin ve ksenobiyotiklerin hücrelerden dışarı atılmasında ve ilaç-ilaç, ilaç-gıda etkileşimlerinde rol oynarlar. Çoğu ilaç etkileşimlerinde, sitokrom P450 ve P-glikoprotein birlikte rol oynar. Hem farmakokinetik ve hem de farmakodinamik etkileşimler, ilaçların farmakolojik etkinliğinde artış ve azalışa neden olabilir. Etkide artış ölüme yol açabilecek düzeyde bir etkileşim oluşturabilirken, etkide azalış ise tedavide başarısızlığa neden olabilir. İlaçlar arasındaki etkileşimin klinik önem arz edip etmeyeceği, etkileşime giren ilaçların terapötik indeks ve vücuttaki farmakokinetik davranış özelliklerinin bilinmesiyle ön görülebilir. Vitaminler, hem beşeri hem de veteriner hekimlikte en fazla suistimal edilen bileşikler arasındadır. İnsan ve hayvanların, besinlerle aldıkları vitaminlere ilave olarak kullanılan vitaminler sağlık açısından risk oluşturmakta ve ilaç etkileşimlerinde çoğu kez vitaminlerin etkisi göz ardı edilmektedir. Vitaminlerle ilaçlar arasındaki etkileşimleri belirlemeye yönelik daha çok deneysel ve klinik çalışmalara ihtiyaç vardır. Bu derlemede, yoğun kullanılan vitaminlerin ilaç etkileşimlerindeki önemi irdelenecektir.

Anahtar Kelimeler: Vitamin; ilaç; etkileşim
ABSTRACT
 Vitamins, which cannot be fully synthesized in the living body, are necessary for physiological functions and are substances that have specific tasks. Drug-drug and drug-food interactions play a major role in the emergence of adverse effects of drugs. The pharmacokinetic based drug interactions are mostly observed at the level of enzyme and transporter transmembrane proteins. Most of the metabolic reactions are carried out by the cytochrome P450 family. Inhibition or induction of enzyme activity alters the concentration of the substrate drug. Pglycoprotein and breast cancer resistance protein, which are ATPbinding cassette transporters, play a role in the elimination of toxic substances and xenobiotics from cells, and in drug-drug and drug-food interactions. The cytochrome P450 enzymes and P-glycoprotein play a role together in many drug interactions. Both pharmacokinetic and pharmacodynamic interactions may cause an increase and decrease in the pharmacological efficacy of drugs. While an increase in effect can cause a level of interaction that can lead to death, a decrease in effect may be the source of treatment failure. Whether the interaction between drugs will be of clinical significance can be predicted by knowing the therapeutic index of the interacting drugs and their pharmacokinetic behavior in the body. Vitamins are the most abused substances in both human and veterinary medicine. The vitamins used in addition to the ones that humans and animals take with foods pose a health risk and the effect of vitamins in drug interactions is often overlooked. More experimental and clinical studies are needed to determine interactions between vitamins and drugs. In this manuscript, the importance of intensely used vitamins in drug interactions was discussed.

Keywords: Vitamin; drug; interaction
REFERENCES:
  1. Clarke SE, Jones BC. Human cytochromes p450 and their role in metabolism-based drug-drug interactions. In: Rodrigues AD, eds. Drug-Drug Interactions. Marcel Dekker: The United States of America; 2002. p.55. [Link] 
  2. Çetin G, Traş B. İlaç davranışında P-glikoprotein'in rolü [Role of P-glycoprotein in Drug Disposition: Review]. Turkiye Klinikleri J Vet Sci. 2011;2(3):196-204. [Link] 
  3. Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A. 2002;99(24):15649-54. [Crossref]  [PubMed]  [PMC] 
  4. Özdemir Z, Traş B. Behaviours of drugs in the milk-a review. Atatürk University J Vet Sci. 2018;13(3):364-72. [Crossref] 
  5. Tomlinson B, Hu M, Lee VW. In vivo assessment of herb-drug interactions: possible utility of a pharmacogenetic approach? Mol Nutr Food Res. 2008;52(7):799-809. [Crossref]  [PubMed] 
  6. LeCluyse EL. Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem Biol Interact. 2001;134(3):283-9. [Crossref]  [PubMed] 
  7. Lin JH. Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. Adv Drug Deliv Rev. 2003;55(1):53-81. [Crossref]  [PubMed] 
  8. Foster BC, Arnason JT, Briggs CJ. Natural health products and drug disposition. Annu Rev Pharmacol Toxicol. 2005;45:203-26. [Crossref]  [PubMed] 
  9. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol. 2004;160(4):339-49. [Crossref]  [PubMed] 
  10. Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica. 2008;38(7-8):802-32. [Crossref]  [PubMed] 
  11. O'Brien FE, O'Connor RM, Clarke G, Dinan TG, Griffin BT, Cryan JF. P-glycoprotein inhibition increases the brain distribution and antidepressant-like activity of escitalopram in rodents. Neuropsychopharmacology. 2013;38(11):2209-19. [Crossref]  [PubMed]  [PMC] 
  12. Pavek P, Merino G, Wagenaar E, Bolscher E, Novotna M, Jonker JW, et al. Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther. 2005;312(1):144-52. [Crossref]  [PubMed] 
  13. Staud F, Pavek P. Breast cancer resistance protein (BCRP/ABCG2). Int J Biochem Cell Biol. 2005;37(4):720-5. [Crossref]  [PubMed] 
  14. Chen Y, Derguini F, Buck J. Vitamin A in serum is a survival factor for fibroblasts. Proc Natl Acad Sci U S A. 1997;94(19):10205-8. [Crossref]  [PubMed]  [PMC] 
  15. Tarapcsák S, Szalóki G, Telbisz Á, Gyöngy Z, Matúz K, Csősz É, et al. Interactions of retinoids with the ABC transporters p-glycoprotein and Breast Cancer Resistance Protein. Sci Rep. 2017;7(1):1-11. [Crossref]  [PubMed]  [PMC] 
  16. Arnold SL, Amory JK, Walsh TJ, Isoherranen N. A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS. J Lipid Res. 2012;53(3):587-98. [Crossref]  [PubMed]  [PMC] 
  17. Veal GJ, Errington J, Rowbotham SE, Illingworth NA, Malik G, Cole M, et al. Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma. Clin Cancer Res. 2013;19(2):469-79. [Crossref]  [PubMed]  [PMC] 
  18. Schmitt-Hoffmann AH, Roos B, Sauer J, Spickermann J, Maares J, Schoetzau A, Meyer I. Pharmacokinetic interactions between alitretinoin and ketoconazole or simvastatin or ciclosporin A. Clin Exp Dermatol. 2011;36 Suppl 2:24-8. [Crossref]  [PubMed] 
  19. Tang J, Fu Q, Wang Y, Racette K, Wang D, Liu F. Vitamin E reverses multidrug resistance in vitro and in vivo. Cancer Lett. 2013;336(1):149-57. [Crossref]  [PubMed]  [PMC] 
  20. Mustacich DJ, Shields J, Horton RA, Brown MK, Reed DJ. Biliary secretion of alpha-tocopherol and the role of the mdr2 P-glycoprotein in rats and mice. Arch Biochem Biophys. 1998;350(2):183-92. [Crossref]  [PubMed] 
  21. Zhou C, Tabb MM, Sadatrafiei A, Grün F, Blumberg B. Tocotrienols activate the steroid and xenobiotic receptor, SXR, and selectively regulate expression of its target genes. Drug Metab Dispos. 2004;32(10):1075-82. [Crossref]  [PubMed] 
  22. Mustacich DJ, Leonard SW, Devereaux MW, Sokol RJ, Traber MG. α-Tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats. Free Radic Biol Med. 2006;41(7):1069-78. [Crossref]  [PubMed] 
  23. Mustacich DJ, Gohil K, Bruno RS, Yan M, Leonard SW, Ho E, et al. Alpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice. J Nutr Biochem. 2009;20(6):469-76. [Crossref]  [PubMed]  [PMC] 
  24. Traber MG, Labut EM, Leonard SW, Lebold KM. α-Tocopherol injections in rats up-regulate hepatic ABC transporters, but not cytochrome P450 enzymes. Free Radic Biol Med. 2011;51(11):2031-40. [Crossref]  [PubMed]  [PMC] 
  25. Podszun MC, Jakobi M, Birringer M, Weiss J, Frank J. The long chain α-tocopherol metabolite α-13'-COOH and γ-tocotrienol induce P-glycoprotein expression and activity by activation of the pregnane X receptor in the intestinal cell line LS 180. Mol Nutr Food Res. 2017;61(3). [Crossref]  [PubMed] 
  26. Parker RS, Sontag TJ, Swanson JE. Cytochrome P4503A-dependent metabolism of tocopherols and inhibition by sesamin. Biochem Biophys Res Commun. 2000;277(3):531-4. [Crossref]  [PubMed] 
  27. Abe C, Uchida T, Ohta M, Ichikawa T, Yamashita K, Ikeda S. Cytochrome P450-dependent metabolism of vitamin E isoforms is a critical determinant of their tissue concentrations in rats. Lipids. 2007;42(7):637-45. [Crossref]  [PubMed] 
  28. Birringer M, Drogan D, Brigelius-Flohe R. Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation. Free Radic Biol Med. 2001;31(2):226-32. [Crossref]  [PubMed] 
  29. Kluth D, Landes N, Pfluger P, Müller-Schmehl K, Weiss K, Bumke-Vogt C, et al. Modulation of Cyp3a11 mRNA expression by alpha-tocopherol but not gamma-tocotrienol in mice. Free Radic Biol Med. 2005;38(4):507-14. [Crossref]  [PubMed] 
  30. Traber MG, Siddens LK, Leonard SW, Schock B, Gohil K, Krueger SK, et al. α-Tocopherol modulates Cyp3a expression, increases γ-CEHC production, and limits tissue γ-tocopherol accumulation in mice fed high γ-tocopherol diets. Free Radic Biol Med. 2005;38(6):773-85. [Crossref]  [PubMed] 
  31. Bauer B, Hartz AM, Fricker G, Miller DS. Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol. 2004;66(3):413-9. [PubMed] 
  32. Johnson CH, Bonzo JA, Cheng J, Krausz KW, Kang DW, Luecke H, et al. Cytochrome P450 regulation by α-tocopherol in Pxr-null and PXR-humanized mice. Drug Metab Dispos. 2013;41(2):406-13. [Crossref]  [PubMed]  [PMC] 
  33. Traber MG. Vitamin E and K interactions--a 50-year-old problem. Nutr Rev. 2008;66(11):624-9. [Crossref]  [PubMed] 
  34. Wheldon GH, Bhatt A, Keller P, Hummler H. d,1-alpha-Tocopheryl acetate (vitamin E): a long term toxicity and carcinogenicity study in rats. Int J Vitam Nutr Res. 1983;53(3):287-96. [PubMed] 
  35. Glynn RJ, Ridker PM, Goldhaber SZ. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: Report from the Women's Health Study. Journal of Vascular Surgery. 2008;47(2):479. [Crossref] 
  36. Hanzawa F, Nomura S, Sakuma E, Uchida T, Ikeda S. Dietary sesame seed and its lignan, sesamin, increase tocopherol and phylloquinone concentrations in male rats. J Nutr. 2013;143(7):1067-73. [Crossref]  [PubMed] 
  37. Farley SM, Leonard SW, Labut EM, Raines HF, Card DJ, Harrington DJ, et al. Vitamin E decreases extra-hepatic menaquinone-4 concentrations in rats fed menadione or phylloquinone. Mol Nutr Food Res. 2012;56(6):912-22. Erratum in: Mol Nutr Food Res. 2013;57(6):1115. [Crossref]  [PubMed] 
  38. Farley SM, Leonard SW, Taylor AW, Birringer M, Edson KZ, Rettie AE, et al. ω-Hydroxylation of phylloquinone by CYP4F2 is not increased by α-tocopherol. Mol Nutr Food Res. 2013;57(10):1785-93. [Crossref]  [PubMed]  [PMC] 
  39. Farley SM, Leonard SW, Stevens JF, Traber MG. Deuterium-labeled phylloquinone fed to α-tocopherol-injected rats demonstrates sensitivity of low phylloquinone-containing tissues to menaquinone-4 depletion. Mol Nutr Food Res. 2014;58(8):1610-9. [Crossref]  [PubMed]  [PMC] 
  40. Hanzawa F, Sakuma E, Nomura S, Uchida T, Oda H, Ikeda S. Excess α-tocopherol decreases extrahepatic phylloquinone in phylloquinone-fed rats but not menaquinone-4 in menaquinone-4-fed rats. Mol Nutr Food Res. 2014;58(8):1601-9. [Crossref]  [PubMed] 
  41. Clarke MW, Burnett JR, Wu JH, Hodgson JM, Ledowski T, Puddey IB, et al. Vitamin E supplementation and hepatic drug metabolism in humans. J Cardiovasc Pharmacol. 2009;54(6):491-6. [Crossref]  [PubMed] 
  42. Bárány P, Stenvinkel P, Ottosson-Seeberger A, Alvestrand A, Morrow J, Roberts JJ 2nd, et al. Effect of 6 weeks of vitamin E administration on renal haemodynamic alterations following a single dose of neoral in healthy volunteers. Nephrol Dial Transplant. 2001;16(3):580-4. [Crossref]  [PubMed] 
  43. Wallert M, Schmölz L, Galli F, Birringer M, Lorkowski S. Regulatory metabolites of vitamin E and their putative relevance for atherogenesis. Redox Biol. 2014;2:495-503. [Crossref]  [PubMed]  [PMC] 
  44. Diepeveen SH, Verhoeven GW, Van Der Palen J, Dikkeschei LD, Van Tits LJ, Kolsters G, et al. Effects of atorvastatin and vitamin E on lipoproteins and oxidative stress in dialysis patients: a randomised-controlled trial. J Intern Med. 2005;257(5):438-45. [Crossref]  [PubMed] 
  45. Podszun MC, Grebenstein N, Spruss A, Schlueter T, Kremoser C, Bergheim I, et al. Dietary α-tocopherol and atorvastatin reduce high-fat-induced lipid accumulation and down-regulate CD36 protein in the liver of guinea pigs. J Nutr Biochem. 2014;25(5):573-9. [Crossref]  [PubMed] 
  46. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-92. [Crossref]  [PubMed] 
  47. Tousoulis D, Antoniades C, Vassiliadou C, Toutouza M, Pitsavos C, Tentolouris C, et al. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail. 2005;7(7):1126-32. [Crossref]  [PubMed] 
  48. Vasankari T, Ahotupa M, Viikari J, Nuotio I, Strandberg T, Vanhanen H, et al. Effect of 12-month statin therapy on antioxidant potential of LDL and serum antioxidant vitamin concentrations. Ann Med. 2004;36(8):618-22. [Crossref]  [PubMed] 
  49. Werba JP, Cavalca V, Veglia F, Massironi P, De Franceschi M, Zingaro L, et al. A new compound-specific pleiotropic effect of statins: modification of plasma gamma-tocopherol levels. Atherosclerosis. 2007;193(1):229-33. [Crossref]  [PubMed] 
  50. Nanayakkara AK, Follit CA, Chen G, Williams NS, Vogel PD, Wise JG. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Sci Rep. 2018;8(1):967. [Crossref]  [PubMed]  [PMC] 
  51. Mohammadzadeh R, Baradaran B, Yousefi B, Valizadeh H, Zakeri-Milani P. Attenuation of intestinal efflux pump thru polymers and preservatives. J Res Pharm. 2019;23(4):632-41. [Crossref] 
  52. Masuda S, Jones G. Promise of vitamin D analogues in the treatment of hyperproliferative conditions. Mol Cancer Ther. 2006;5(4):797-808. [Crossref]  [PubMed] 
  53. Chow EC, Maeng HJ, Liu S, Khan AA, Groothuis GM, Pang KS. 1alpha,25-Dihydroxyvitamin D(3) triggered vitamin D receptor and farnesoid X receptor-like effects in rat intestine and liver in vivo. Biopharm Drug Dispos. 2009;30(8):457-75. [Crossref]  [PubMed] 
  54. Kim RB. Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab Rev. 2002;34(1-2):47-54. [Crossref]  [PubMed] 
  55. Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai I, et al. Oseltamivir (Tamiflu) efflux transport at the blood-brain barrier via P-glycoprotein. Drug Metab Dispos. 2008;36(1):6-9. [Crossref]  [PubMed] 
  56. Chow EC, Durk MR, Cummins CL, Pang KS. 1Alpha,25-dihydroxyvitamin D3 up-regulates P-glycoprotein via the vitamin D receptor and not farnesoid X receptor in both fxr(-/-) and fxr(+/+) mice and increased renal and brain efflux of digoxin in mice in vivo. J Pharmacol Exp Ther. 2011;337(3):846-59. [Crossref]  [PubMed] 
  57. Fan J, Liu S, Du Y, Morrison J, Shipman R, Pang KS. Up-regulation of transporters and enzymes by the vitamin D receptor ligands, 1alpha,25-dihydroxyvitamin D3 and vitamin D analogs, in the Caco-2 cell monolayer. J Pharmacol Exp Ther. 2009;330(2):389-402. [Crossref]  [PubMed] 
  58. Margier M, Collet X, le May C, Desmarchelier C, André F, Lebrun C, et al. ABCB1 (P-glycoprotein) regulates vitamin D absorption and contributes to its transintestinal efflux. FASEB J. 2019;33(2):2084-2094. [Crossref]  [PubMed] 
  59. Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, et al. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos. 2005;33(1):165-74. [Crossref]  [PubMed] 
  60. Kota BP, Allen JD, Roufogalis BD. The effect of vitamin D3 and ketoconazole combination on VDR-mediated P-gp expression and function in human colon adenocarcinoma cells: implications in drug disposition and resistance. Basic Clin Pharmacol Toxicol. 2011;109(2):97-102. [Crossref]  [PubMed] 
  61. Khan AA, Chow ECY, van Loenen-Weemaes AMA, Porte RJ, Pang KS, Groothuis GM. Comparison of effects of VDR versus PXR, FXR and GR ligands on the regulation of CYP3A isozymes in rat and human intestine and liver. Eur J Pharm Sci. 2009;37(2):115-25. [Crossref]  [PubMed] 
  62. Chan LN. Drug-nutrient interactions. JPEN J Parenter Enteral Nutr. 2013;37(4):450-9. [Crossref]  [PubMed] 
  63. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160-4. [Crossref]  [PubMed] 
  64. Montagnani M, Loré F, Di Cairano G, Gonnelli S, Ciuoli C, Montagnani A, et al. Effects of pravastatin treatment on vitamin D metabolites. Clin Ther. 1994;16(5):824-9. [PubMed] 
  65. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565-81. [Crossref]  [PubMed] 
  66. Robien K, Oppeneer SJ, Kelly JA, Hamilton-Reeves JM. Drug-vitamin D interactions: a systematic review of the literature. Nutr Clin Pract. 2013;28(2):194-208. [Crossref]  [PubMed]  [PMC] 
  67. Zhou S, Chan E, Lim LY, Boelsterli UA, Li SC, Wang J, et al. Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab. 2004;5(5):415-42. [Crossref]  [PubMed] 
  68. Zhou SF, Xue CC, Yu XQ, Li C, Wang G. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007;29(6):687-710. [Crossref]  [PubMed] 
  69. Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE, Dusso AS. HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. AIDS. 2003;17(4):513-20. [Crossref]  [PubMed] 
  70. Wyatt CL, Jensen LS, Rowland GN 3rd. Effect of cimetidine on eggshell quality and plasma 25-hydroxycholecalciferol in laying hens. Poult Sci. 1990;69(11):1892-9. [Crossref]  [PubMed] 
  71. Odes HS, Fraser GM, Krugliak P, Lamprecht SA, Shany S. Effect of cimetidine on hepatic vitamin D metabolism in humans. Digestion. 1990;46(2):61-4. [Crossref]  [PubMed] 
  72. Gröber U. Interactions between drugs and micronutrients. Trace Elements & Electrolytes. 2010;27(1):1-9. [Crossref] 
  73. Zannoni VG, Sato PH. Interaction with drugs and environmental chemicals. Effects of ascorbic acid on microsomal drug metabolism. Ann N Y Acad Sci. 1975;258:119-31. [Crossref]  [PubMed] 
  74. Dysken MW, Cumming RJ, Channon RA, Davis JM. Drug interaction between ascorbic acid and fluphenazine. JAMA. 1979;241(19): 2008. [Crossref]  [PubMed] 
  75. Golde DW. Vitamin C in cancer. Integr Cancer Ther. 2003;2(2):158-9. [Crossref]  [PubMed] 
  76. Grad JM, Cepero E, Boise LH. Mitochondria as targets for established and novel anti-cancer agents. Drug Resist Updat. 2001;4(2):85-91. [Crossref]  [PubMed] 
  77. Karasavvas N, Cárcamo JM, Stratis G, Golde DW. Vitamin C protects HL60 and U266 cells from arsenic toxicity. Blood. 2005;105(10): 4004-12. [Crossref]  [PubMed]  [PMC] 
  78. Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, et al. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res. 2008;68(19):8031-8. [Crossref]  [PubMed]  [PMC] 
  79. McColl KE. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol. 2009;104 Suppl 2:S5-9. [Crossref]  [PubMed] 
  80. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr. 2003;77(6):1352-60. [Crossref]  [PubMed] 
  81. Huang SN, Swaan PW. Involvement of a receptor-mediated component in cellular translocation of riboflavin. J Pharmacol Exp Ther. 2000;294(1):117-25. [PubMed] 
  82. van Herwaarden AE, Wagenaar E, Merino G, Jonker JW, Rosing H, Beijnen JH, et al. Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol. 2007;27(4):1247-53. [Crossref]  [PubMed]  [PMC] 
  83. Lichtenstein NS, Goldman ID. Riboflavin-methotrexate interactions. Photochemical reaction and competition for transport in the L1210 mouse leukemia cell. Biochem Pharmacol. 1970;19(4):1229-39. [Crossref]  [PubMed] 
  84. Vora B, Green EAE, Khuri N, Ballgren F, Sirota M, Giacomini KM. Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3). Am J Clin Nutr. 2020;111(1):110-121. [Crossref]  [PubMed]  [PMC] 
  85. Liang X, Chien HC, Yee SW, Giacomini MM, Chen EC, Piao M, et al. Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015;12(12):4301-10. [Crossref]  [PubMed]  [PMC] 
  86. Giacomini MM, Hao J, Liang X, Chandrasekhar J, Twelves J, Whitney JA, et al. Interaction of 2,4-diaminopyrimidine-containing drugs including fedratinib and trimethoprim with thiamine transporters. Drug Metab Dispos. 2017;45(1):76-85. [Crossref]  [PubMed] 
  87. Sagar M, Janczewska I, Ljungdahl A, Bertilsson L, Seensalu R. Effect of CYP2C19 polymorphism on serum levels of vitamin B12 in patients on long-term omeprazole treatment. Aliment Pharmacol Ther. 1999;13(4):453-8. [Crossref]  [PubMed] 

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1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com