Main Article Content
Curcuminoids, the major components of Curcuma longa L. (turmeric), have inhibitory properties against P-glycoprotein, an efflux transporter found in the intestine. It is reasonable to hypothesize that the inhibition of P-glycoprotein-mediated transport by curcuminoids can cause an increase in plasma concentrations of P-glycoprotein substrates, such as digoxin, in the human body. In our previous randomized crossover study, we observed an increase in digoxin plasma concentrations following concomitant use of a turmeric crude extract equivalent to 1,000 mg of curcuminoids per day in a majority of healthy male volunteers. However, there were two volunteers whose pharmacokinetic changes were opposite to those of the other volunteers; that is, digoxin plasma concentrations were markedly decreased after the concomitant use of the turmeric crude extract. In the present article, we report the results of our repeated experiment with these two volunteers using a different digoxin formulation (i.e., digoxin elixir). With digoxin elixir, the unusual pharmacokinetic pattern was somewhat similar to that observed in the corresponding experiment with digoxin tablets. The consistent results between initial and repeated experiments ensured that the unusual pharmacokinetic herb-drug interaction was not mainly attributable to an abnormal disintegration or dissolution of the digoxin tablets. Precaution should be taken when the turmeric crude extract is concurrently taken with P-glycoprotein substrates. Not only an increase in plasma concentrations of P-glycoprotein substrates, but also a decrease in plasma concentrations of such substrates could occur.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Upon acceptance of an article, the Pharmacological and Therapeutic Society of Thailand will have exclusive right to publish and distribute the article in all forms and media and grant rights to others. Authors have rights to use and share their own published articles.
Hay E, Lucariello A, Contieri M, Esposito T, De Luca A, Guerra G, et al. Therapeutic effects of turmeric in several diseases: An overview. Chem Biol Interact. 2019;310:108729.
Hewlings SJ, Kalman DS. Curcumin: a review of its effects on human health. Foods. 2017;6(10):92.
Sharifi-Rad J, Rayess YE, Rizk AA, Sadaka C, Zgheib R, Zam W, et al. Turmeric and its major compound curcumin on health: bioactive effects and safety profiles for food, pharmaceutical, biotechnological and medicinal applications. Front Pharmacol. 2020;11:01021.
Amalraj A, Pius A, Gopi S, Gopi S. Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives-A review. J Tradit Complement Med. 2016;7(2):205-233.
Pothitirat W, Gritsanapan W. Quantitative analysis of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the crude curcuminoid extract from Curcuma longa in Thailand by TLC-densitometry. Mahidol U J Pharmaceutic Sci. 2005;32(1-2):23-30.
Romiti N, Tongiani R, Cervelli F, Chieli E. Effects of curcumin on P-glycoprotein in primary cultures of rat hepatocytes. Life Sci. 1998;62(25):2349-2358.
Ampasavate C, Sotanaphun U, Phattanawasin P, Piyapolrungroj N. Effects of Curcuma spp. on P-glycoprotein function. Phytomedicine. 2010;17(7):506-512.
Limtrakul P, Anuchapreeda S, Buddhasukh D. Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC Cancer. 2004;4:13.
Teng YN, Hsieh YW, Hung CC, Lin HY. Demethoxycurcumin modulates human P-glycoprotein function via uncompetitive inhibition of ATPase hydrolysis activity. J Agric Food Chem. 2015;63(3):847-855.
Zhang W, Tan TM, Lim LY. Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmaco-kinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos. 2007;35(1): 110-115.
Sagnou M, Novikov FN, Ivanova ES, Alexiou P, Stroylov VS, Titov IY, et al. Novel curcumin derivatives as P-glycoprotein inhibitors: Molecular modeling, synthesis and sensitization of multidrug resistant cells to doxorubicin. Eur J Med Chem. 2020;198:112331.
Fan X, Zhang C, Liu DB, Yan J, Liang HP. The clinical applications of curcumin: current state and the future. Curr Pharm Des. 2013;19(11):2011-2031.
Lopes-Rodrigues V, Sousa E, Vasconcelos MH. Curcumin as a modulator of P-glycoprotein in cancer: challenges and perspectives. pharmaceuticals (basel). 2016; 9(4):71.
Oliveira AS, Sousa E, Vasconcelos MH, Pinto M. Curcumin: a natural lead for potential new drug candidates. Curr Med Chem. 2015;22(36):4196-4232.
Si M, Zhao J, Li X, Tian JG, Li YG, Li JM. Reversion effects of curcumin on multidrug resistance of MNNG/HOS human osteo-sarcoma cells in vitro and in vivo through regulation of P-glycoprotein. Chin Med J (Engl). 2013;126(21):4116-4123.
Lopes-Rodrigues V, Oliveira A, Correia-da-Silva M, Pinto M, Lima RT, Sousa E, et al. A novel curcumin derivative which inhibits P-glycoprotein, arrests cell cycle and induces apoptosis in multidrug resistance cells. Bioorg Med Chem. 2017;25(2):581-596.
Dash TK, Konkimalla VB. Comparative study of different nano-formulations of curcumin for reversal of doxorubicin resistance in K562R cells. Pharm Res. 2017;34(2):279-289.
Mansouri K, Rasoulpoor S, Daneshkhah A, Abolfathi S, Salari N, Mohammadi M, et al. Clinical effects of curcumin in enhancing cancer therapy: A systematic review. BMC Cancer. 2020;20(1):791.
Tan BL, Norhaizan ME. Curcumin combination chemotherapy: the implication and efficacy in cancer. Molecules. 2019; 24(14):2527.
Englund G, Hallberg P, Artursson P, Michaëlsson K, Melhus H. Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring. BMC Med. 2004;2:8.
Nader AM, Foster DR. Suitability of digoxin as a P-glycoprotein probe: implications of other transporters on sensitivity and specificity. J Clin Pharmacol. 2014;54(1):3-13.
Meneses-Lorente G, Fowler S, Guerini E, Kowalski K, Chow-Maneval E, Yu L, et al. In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK). Invest New Drugs. 2021.
Ou YC, Tang Z, Novotny W, Tawashi M, Li TK, Coleman HA, et al. Evaluation of drug interaction potential of zanubrutinib with cocktail probes representative of CYP3A4, CYP2C9, CYP2C19, P-gp and BCRP. Br J Clin Pharmacol. 2021;87(7):2926-2936.
Wiebe ST, Giessmann T, Hohl K, Schmidt-Gerets S, Hauel E, Jambrecina A, et al. Validation of a drug transporter probe cocktail using the prototypical inhibitors rifampin, probenecid, verapamil, and cimetidine. Clin Pharmacokinet. 2020; 59(12):1627-1639.
Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine. Circulation. 1999;99(4):552-557.
Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest. 1999; 104(2):147-153.
Koonrungsesomboon N, Hanprasertpong N, Potikanond S, Karbwang J, Teekachunhatean S. Divergent effects of turmeric crude extract on P-glycoprotein activity in healthy male subjects: a randomized crossover study. J Med Assoc Thai. 2018;101(3):313-321.
Bahramsoltani R, Rahimi R, Farzaei MH. Pharmacokinetic interactions of curcuminoids with conventional drugs: A review. J Ethno-pharmacol. 2017;209:1-12.
Dogra A, Bhatt S, Magotra A, Sharma A, Kotwal P, Gour A, et al. Intervention of curcumin on oral pharmacokinetics of daclatasvir in rat: a possible risk for long-term use. Phytother Res. 2018;32(10): 1967-1974.
Okura T, Ibe M, Umegaki K, Shinozuka K, Yamada S. Effects of dietary ingredients on function and expression of P-glycoprotein in human intestinal epithelial cells. Biol Pharm Bull. 2010;33(2):255-259.
Chearwae W, Anuchapreeda S, Nandigama K, Ambudkar SV, Limtrakul P. Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from turmeric powder. Biochem Pharmacol. 2004;68(10):2043-2052.
Juan H, Terhaag B, Cong Z, Bi-Kui Z, Rong-Hua Z, Feng W, et al. Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers. Eur J Clin Pharmacol. 2007;63(7):663-668.
Juan H, Jing T, Wan-Hua Y, Juan S, Xiao-Lei L, Wen-Xing P. P-gp induction by curcumin: an effective antidotal pathway. J Bioequiv Bioavail. 2013; 5(6):236-241.
He X, Mo L, Li ZY, Tan ZR, Chen Y, Ouyang DS. Effects of curcumin on the pharmacokinetics of talinolol in human with ABCB1 polymorphism. Xenobiotica. 2012;42(12):1248-1254.
Ireson CR, Jones DJ, Orr S, Coughtrie MW, Boocock DJ, Williams ML, et al. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomarkers Prev. 2002; 11(1):105-111.
Hou XL, Takahashi K, Tanaka K, Tougou K, Qiu F, Komatsu K, et al. Curcuma drugs and curcumin regulate the expression and function of P-gp in Caco-2 cells in completely opposite ways. Int J Pharm. 2008;358(1-2):224-229.
Yue GG, Cheng SW, Yu H, Xu ZS, Lee JK, Hon PM, et al. The role of turmerones on curcumin transportation and P-glycoprotein activities in intestinal Caco-2 cells. J Med Food. 2012;15(3):242-252.
Kiley CA, Cragin DJ, Roth BJ. Omeprazole-associated digoxin toxicity. South Med J. 2007;100(4):400-402.
Hsieh YW, Huang CY, Yang SY, Peng YH, Yu CP, Chao PD, et al. Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies. Sci Rep. 2014;4: 6587.
Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res. 1999;16(3):408-414.
Thelen K, Dressman JB. Cytochrome P450-mediated metabolism in the human gut wall. J Pharm Pharmacol. 2009;61(5): 541-558.