Drug interactions of cola-containing drinks

Published:February 09, 2019DOI:https://doi.org/10.1016/j.clnu.2019.01.029


      Cola-containing drinks (CCDs) are among the most common drinks in the world. There are some reports on interactions between CCDs and some drugs. However, there is no review on reported and possible interactions of CCDs. Thus, this paper attempted to provide a comprehensive review on this subject. It is well-accepted that CCDs are acidic and contain caffeine. It has been suggested that these two properties potentiate interactions of CCDs with different drugs in the context of both pharmacodynamics and pharmacokinetic, which includes drug absorption, metabolism, and renal excretion of drugs. It has been shown that serum concentrations of MTX, clozapine, carbamazepine, phenytoin, and ibuprofen increased following CCD consumption; these interactions can be toxic. Additionally, it has been reported that serum levels of lithium and warfarin were decreased and their efficacy reduced when simultaneously administered with CCDs. Serum concentrations of erlotinib and different azoles, including itraconazol, posaconazole, and ketoconazole, have been shown to increase when these drugs were co-administered with a CCD. As proposed and discussed here, CCDs have the potential for interactions with numerous other drugs and thus clinicians should be aware of reported and potential interactions of CCDs with various medications in order to avoid adverse reactions and achieve expected clinical response.


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        • Rodríguez Alonso P.
        • Del Pozo de la Calle S.
        • Valero Gaspar T.
        • Ruiz Moreno E.
        • Ávila Torres J.M.
        • Varela-Moreiras G.
        Fifty years of beverages consumption trends in Spanish households.
        Nutr Hosp. 2016; 33: 316
        • Gornicka M.
        • Pierzynowska J.
        • Kaniewska E.
        • Kossakowska K.
        • Wozniak A.
        School pupils and university students surveyed for drinking beverages containing caffeine.
        Rocz Panstw Zakl Hig. 2014; 65: 113-117
        • Alquimim A.F.
        • Barral A.B.
        • Gomes K.C.
        • Rezende M.C.
        Evaluation of labor-related and physical risk factors for cardiovascular disease in drivers of urban transport buses in Montes Claros in the state of Minas Gerais.
        Ciência Saúde Coletiva. 2012; 17: 2151-2158
        • Mirmiran P.
        • Azadbakht L.
        • Azizi F.
        Dietary behaviour of Tehranian adolescents does not accord with their nutritional knowledge.
        Publ Health Nutr. 2007; 10: 897-901
        • Barone J.J.
        • Roberts H.R.
        Caffeine consumption.
        Food Chem Toxicol – Int J Publ Br Ind Biol Res Assoc. 1996; 34: 119-129
        • Bunker M.L.
        • McWilliams M.
        Caffeine content of common beverages.
        J Am Diet Assoc. 1979; 74: 28-32
        • Kralovec K.
        • Fartacek R.
        • Ploderl M.
        • Fartacek C.
        • Aichhorn W.
        Low serum lithium associated with immoderate use of Coca-Cola Zero.
        J Clin Psychopharmacol. 2011; 31: 543-544
        • Cascorbi I.
        Drug interactions--principles, examples and clinical consequences.
        Dtsch Arzteblatt Int. 2012; 109 (quiz 56): 546-555
        • Kot M.
        • Daniel W.A.
        Caffeine as a marker substrate for testing cytochrome P450 activity in human and rat.
        Pharmacol Rep. 2008; 60: 789-797
        • Mansbridge B.
        • Fisher S.
        Public knowledge and attitudes about diazepam.
        Psychopharmacology. 1984; 82: 225-228
        • Czok G.
        Reciprocal action between caffeine, other stimulants and drugs.
        Z Ernahrungswiss. 1980; 19: 290-295
        • Zhao Y.H.
        • Abraham M.H.
        • Le J.
        • Hersey A.
        • Luscombe C.N.
        • Beck G.
        • et al.
        Rate-limited steps of human oral absorption and QSAR studies.
        Pharmaceut Res. 2002; 19: 1446-1457
        • Schanker L.S.
        Mechanisms of drug absorption and distribution.
        Annu Rev Pharmacol. 1961; 1: 29-45
        • Van Leeuwen R.W.F.
        • Van Gelder T.
        • Aerts J.G.
        • Mathijssen R.H.J.
        Reply to N. Singh et al.
        J Clin Oncol. 2016; 34: 4054
        • Walravens J.
        • Brouwers J.
        • Spriet I.
        • Tack J.
        • Annaert P.
        • Augustijns P.
        Effect of pH and comedication on gastrointestinal absorption of posaconazole: monitoring of intraluminal and plasma drug concentrations.
        Clin Pharmacokinet. 2011; 50: 725-734
        • Lange D.
        • Pavao J.H.
        • Wu J.
        • Klausner M.
        Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers.
        J Clin Pharmacol. 1997; 37: 535-540
        • Chin T.W.
        • Loeb M.
        • Fong I.W.
        Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole.
        AAC (Antimicrob Agents Chemother). 1995; 39: 1671-1675
        • Kondal A.
        • Garg S.K.
        Influence of acidic beverage (Coca-Cola) on pharmacokinetics of ibuprofen in healthy rabbits.
        Indian J Exp Biol. 2003; 41: 1322-1324
        • Levy G.
        pharmacokinetic approaches to the study of drug interactions.
        Ann N Y Acad Sci. 1976; : 24-39
        • Chiwele I.
        • Jones B.E.
        • Podczeck F.
        The shell dissolution of various empty hard capsules.
        Chem Pharm Bull. 2000; 48: 951-956
        • Doude van Troostwijk L.J.
        • Koopmans R.P.
        • Vermeulen H.D.
        • Guchelaar H.J.
        CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients.
        Eur J Pharm Sci – Off J Eur Fed Pharmaceut Sci. 2003; 20: 451-457
        • Prior T.I.
        • Baker G.B.
        Interactions between the cytochrome P450 system and the second-generation antipsychotics.
        J Psychiatry Neurosci: JPN. 2003; 28: 99-112
        • Sutrisna E.
        The impact of CYP1A2 and CYP2E1 genes polymorphism on theophylline response.
        J Clin Diagn Res : J Clin Diagn Res. 2016; 10: FE01-FE3
        • Wild M.J.
        • McKillop D.
        • Butters C.J.
        Determination of the human cytochrome P450 isoforms involved in the metabolism of zolmitriptan.
        Xenobiotica: Fate Foreign Comp Biol Sys. 1999; 29: 847-857
        • Al Hadithy A.
        • Leeffers E.
        • Bruggeman R.
        Clozapine levels might be affected by excessive cola consumption.
        J Clin Psychopharmacol. 2012; 32: 717-719
        • Monks T.J.
        • Lawrie C.A.
        • Caldwell J.
        The effect of increased caffeine intake on the metabolism and pharmacokinetics of theophylline in man.
        Biopharm Drug Dispos. 1981; 2: 31-37
        • de Vries E.G.
        • Meyer C.
        • Strubbe M.
        • Mulder N.H.
        Influence of various beverages on urine acid output.
        Cancer Res. 1986; 46: 430-432
        • Bauters T.
        • Lammens T.
        • Belin P.
        • Benoit Y.
        • Robays H.
        • de Moerloose B.
        Delayed elimination of methotrexate by cola beverages in a pediatric acute lymphoblastic leukemia population.
        Leuk Lymphoma. 2013; 54: 1094-1096
        • Bardal S.K.
        • Waechter J.E.
        • Martin D.S.
        Chapter 2 - pharmacokinetics. Applied pharmacology.
        Content Repository Only!, Philadelphia2011: 17-34
        • Fukunaga K.
        • Saito M.
        • Muto M.
        • Mishima K.
        • Fujiwara M.
        • Orito K.
        Effects of urine pH modification on pharmacokinetics of phenobarbital in healthy dogs.
        J Vet Pharmacol Therapeut. 2008; 31: 431-436
        • Santucci R.
        • Leveque D.
        • Herbrecht R.
        Cola beverage and delayed elimination of methotrexate.
        Br J Clin Pharmacol. 2010; 70: 762-764
        • Rieg T.
        • Steigele H.
        • Schnermann J.
        • Richter K.
        • Osswald H.
        • Vallon V.
        Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine.
        J Pharmacol Exp Therapeut. 2005; 313: 403-409
        • Shirley D.G.
        • Walter S.J.
        • Noormohamed F.H.
        Natriuretic effect of caffeine: assessment of segmental sodium reabsorption in humans.
        Clin Sci. 2002; 103 (London, England : 1979): 461-466
        • Oliveira J.L.d.
        • Silva Júnior G.B.d.
        • Abreu K.L.S.d.
        • Rocha NdA.
        • Franco L.F.L.G.
        • Araújo S.M.H.A.
        • et al.
        Nefrotoxicidade por lítio.
        Rev Assoc Méd Bras. 2010; 56: 600-606
        • Gee S.
        • Dixon T.
        • Docherty M.
        • Shergill S.S.
        Optimising plasma levels of clozapine during metabolic interactions: a review and case report with adjunct rifampicin treatment.
        BMC Psychiatry. 2015; 15: 195
        • Malhotra S.
        • Dixit R.K.
        • Garg S.K.
        Effect of an acidic beverage (Coca-Cola) on the pharmacokinetics of carbamazepine in healthy volunteers.
        Methods Find Exp Clin Pharmacol. 2002; 24: 31-33
        • Karmakar S.
        • Biswas S.
        • Bera R.
        • Mondal S.
        • Kundu A.
        • Ali M.A.
        • et al.
        Beverage-induced enhanced bioavailability of carbamazepine and its consequent effect on antiepileptic activity and toxicity.
        J Food Drug Anal. 2015; 23: 327-334
        • Jankiewicz K.
        • Chroscinska-Krawczyk M.
        • Blaszczyk B.
        • Czuczwar S.J.
        [Caffeine and antiepileptic drugs: experimental and clinical data].
        Przegl Lek. 2007; 64: 965-967
        • Clapauch S.H.
        • Benchimol-Barbosa P.R.
        Warfarin resistance and caffeine containing beverages.
        Int J Cardiol. 2012; 156: e4-e5
        • Lakshmi R.
        • Anitha S.
        • N Anila K.
        • R Roshni P.
        Warfarin resistance-mechanisms and management.
        Int J Pharm Sci Res. 2012;
        • Sattar A.
        • Willman J.E.
        • Kolluri R.
        Possible warfarin resistance due to interaction with ascorbic acid: case report and literature review.
        Am J Health Syst Pharm: AJHP – Off J Am Soc Health-Sys Pharm. 2013; 70: 782-786
        • Kolade Y.T.
        • Babalola C.P.
        • Olaniyi A.A.
        • Scriba G.K.
        Effect of kolanut on the pharmacokinetics of the antimalarial drug halofantrine.
        Eur J Clin Pharmacol. 2008; 64: 77-81
        • Neuvonen P.
        The effect of magnesium hydroxide on the oral absorption of ibuprofen, ketoprofen and diclofenac.
        Br J Clin Pharmacol. 1991; 31: 263-266
        • Kondal A.
        • Garg S.K.
        Influence of an acidic beverage (Coca-Cola) on the pharmacokinetics of phenytoin in healthy rabbits.
        Methods Find Exp Clin Pharmacol. 2003; 25: 823-825
        • Kulshrestha V.K.
        • Thomas M.
        • Wadsworth J.
        • Richens A.
        Interaction between phenytoin and antacids.
        Br J Clin Pharmacol. 1978; 6: 177-179
        • Bae S.K.
        • Park S.J.
        • Shim E.J.
        • Mun J.H.
        • Kim E.Y.
        • Shin J.G.
        • et al.
        Increased oral bioavailability of itraconazole and its active metabolite, 7-hydroxyitraconazole, when coadministered with a vitamin C beverage in healthy participants.
        J Clin Pharmacol. 2011; 51: 444-451
        • Lange D.
        • Pavao J.H.
        • Jacqmin P.
        • Woestenborghs R.
        • Ding C.
        • Klausner M.
        The effect of coadministration of a cola beverage on the bioavailability of itraconazole in patients with acquired immunodeficiency syndrome.
        Curr Ther Res Clin Exp. 1997; 58: 202-212
        • Fotaki N.
        • Klein S.
        Mechanistic understanding of the effect of PPIs and acidic carbonated beverages on the oral absorption of itraconazole based on absorption modeling with appropriate in vitro data.
        Mol Pharm. 2013; 10: 4016-4023
        • Jaruratanasirikul S.
        • Kleepkaew A.
        Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole.
        Eur J Clin Pharmacol. 1997; 52: 235-237
        • Wimberley S.L.
        • Haug 3rd, M.T.
        • Shermock K.M.
        • Qu A.
        • Maurer J.R.
        • Mehta A.C.
        • et al.
        Enhanced cyclosporine-itraconazole interaction with cola in lung transplant recipients.
        Clin Transpl. 2001; 15: 116-122
        • Retamero A.
        • Conde-Estévez D.
        Erlotinib and acid suppressive agents: is it worth to take a coke?.
        Ann Oncol. 2017; 28: 192-193
        • Van Leeuwen R.W.F.
        • Peric R.
        • Hussaarts K.G.A.M.
        • Kienhuis E.
        • Ijzerman N.S.
        • De Bruijn P.
        • et al.
        Influence of the acidic beverage cola on the absorption of erlotinib in patients with non-small-cell lung cancer.
        J Clin Oncol. 2016; 34: 1309-1314
        • Planchard D.
        Can an acidic beverage reduce interactions between proton pump inhibitors and erlotinib?.
        J Clin Oncol. 2016; 34: 1292-1294
        • Gruber A.
        • Czejka M.
        • Buchner P.
        • Kitzmueller M.
        • Kirchbaumer Baroian N.
        • Dittrich C.
        • et al.
        Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model.
        Cancer Chemother Pharmacol. 2018; 81: 763-771
        • Layrisse M.
        • Martinez-Torres C.
        • Renzi M.
        • Velez F.
        • Gonzalez M.
        Sugar as a vehicle for iron fortification.
        Am J Clin Nutr. 1976; 29: 8-18
        • Collings R.
        • Fairweather-Tait S.J.
        • Dainty J.R.
        • Roe M.A.
        Low-pH cola beverages do not affect women's iron absorption from a vegetarian meal.
        J Nutr. 2011; 141: 805-808