Planta Med 2013; 79(11): 971-977
DOI: 10.1055/s-0032-1328652
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Curcumin Alters the Pharmacokinetics of Warfarin and Clopidogrel in Wistar Rats but Has No Effect on Anticoagulation or Antiplatelet Aggregation

An-Chang Liu
1   Qilu Hospital of Shandong University, Jinan, P. R. China
,
Li-Xia Zhao
1   Qilu Hospital of Shandong University, Jinan, P. R. China
,
Hong-Xiang Lou
2   School of Pharmaceutical Sciences, Shandong University, Jinan, P. R. China
› Author Affiliations
Further Information

Publication History

received 10 December 2012
revised 07 May 2013

accepted 12 May 2013

Publication Date:
27 June 2013 (online)

Abstract

This study examined the effects of curcumin on the pharmacokinetic and pharmacodynamic properties of warfarin and clopidogrel in Wistar rats. Results showed that oral administration of curcumin at 25 mg/kg, 50 mg/kg, and 100 mg/kg for 7 days had no substantial effects on the pharmacodynamics of warfarin and clopidogrel in this animal model. However, oral administration of 100 mg/kg curcumin for 7 days significantly increased the AUC0-∞ and Cmax of the two drugs (by × 1.6 and × 1.5, respectively, for warfarin, and × 1.61 and × 1.81, respectively, for clopidogrel carboxylic acid). However, compared to warfarin alone, different doses of curcumin combined with warfarin had no effects on the prothrombin time in rats. Similarly, a combination of curcumin and clopidogrel had no significant effect on the maximum platelet aggregation rate of rats compared with the use of clopidogrel alone. This work demonstrated that preadministration of 100 mg/kg curcumin affected the pharmacokinetics of warfarin and clopidogrel but had no effect on pharmacodynamic parameters such as anticoagulation rate and antiplatelet aggregation.

 
  • References

  • 1 Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 1998; 280: 1569-1575
  • 2 Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary SE. Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol 2000; 18: 2505-2514
  • 3 Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA 2001; 286: 208-216
  • 4 Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002; 287: 337-344
  • 5 Wold RS, Lopez ST, Yau CL, Butler LM, Pareo-Tubbeh SL, Waters DL, Garry PJ, Baumgartner RN. Increasing trends in elderly personsʼ use of nonvitamin, nonmineral dietary supplements and concurrent use of medications. J Am Diet Assoc 2005; 105: 54-63
  • 6 Shahrokh LE, Lukaszuk JM, Prawitz AD. Elderly herbal supplement users less satisfied with medical care than nonusers. J Am Diet Assoc 2005; 105: 1138-1140
  • 7 Kim DC, Lee W, Bae JS. Vascular anti-inflammatory effects of curcumin on HMGB1-mediated responses in vitro . Inflamm Res 2011; 60: 1161-1168
  • 8 Karaman M, Firinci F, Cilaker S, Uysal P, Tugyan K, Yilmaz O, Uzuner N, Karaman O. Anti-inflammatory effects of curcumin in a murine model of chronic asthma. Allergol Immunopathol (Madr) 2012; 40: 210-214
  • 9 Li Y, Revalde JL, Reid G, Paxton JW. Modulatory effects of curcumin on multi-drug resistance-associated protein 5 in pancreatic cancer cells. Cancer Chemother Pharmacol 2011; 68: 603-610
  • 10 Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, Marczylo TH, Morgan B, Hemingway D, Plummer SM, Pirmohamed M, Gescher AJ, Steward WP. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 2004; 10: 6847-6854
  • 11 Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC, Hsieh CY. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001; 21: 2895-2900
  • 12 Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V, Kurzrock R. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 2008; 14: 4491-4499
  • 13 Li C, Kim DK. Effects of curcumin on the pharmacokinetics of loratadine in rats: possible role of CYP3A4 and P-glycoprotein inhibition by curcumin. Biomol Ther 2011; 19: 364-370
  • 14 Lee CK, Ki SH, Choi JS. Effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats: possible role of intestinal CYP3A and P-gp inhibition by curcumin. Biopharm Drug Dispos 2011; 32: 245-251
  • 15 Liu AC, Zhao LX, Xing J, Liu T, Du FY, Lou HX. Pre-treatment with curcumin enhances plasma concentrations of losartan and its metabolite EXP3174 in rats. Biol Pharm Bull 2012; 35: 145-150
  • 16 Gage BF, Milligan PE. Pharmacology and pharmacogenetics of warfarin and other coumarins when used with supplements. Thromb Res 2005; 117: 55-59 discussion 65–67
  • 17 Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee M, Moss J. Brief communication: American ginseng reduces warfarinʼs effect in healthy patients: a randomized, controlled trial. Ann Intern Med 2004; 141: 23-27
  • 18 Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q10 and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients. A randomised, double blind, placebo-crossover trial. Thromb Haemost 2002; 87: 1075-1076
  • 19 Tang M, Mukundan M, Yang J, Charpentier N, LeCluyse EL, Black C, Yang D, Shi D, Yan B. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J Pharmacol Exp Ther 2006; 319: 1467-1476
  • 20 Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010; 38: 92-99
  • 21 Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52: 1557-1563
  • 22 Farid NA, Payne CD, Small DS, Winters KJ, Ernest 2nd CS, Brandt JT, Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 2007; 81: 735-741
  • 23 Jiang J, Wang W, Sun YJ, Hu M, Li F, Zhu DY. Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage. Eur J Pharmacol 2007; 561: 54-62
  • 24 Yang C, Zhang X, Fan H, Liu Y. Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res 2009; 1282: 133-141
  • 25 Mohanty I, Singh Arya D, Dinda A, Joshi S, Talwar KK, Gupta SK. Protective effects of Curcuma longa on ischemia-reperfusion induced myocardial injuries and their mechanisms. Life Sci 2004; 75: 1701-1711
  • 26 Volak LP, Ghirmai S, Cashman JR, Court MH. Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos 2008; 36: 1594-1605
  • 27 Hou XL, Takahashi K, Tanaka K, Tougou K, Qiu F, Komatsu K, Azuma J. 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: 224-229
  • 28 Zhang W, Tan TM, Lim LY. Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos 2007; 35: 110-115
  • 29 Wadelius M, Sorlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, Wadelius C, Melhus H. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 2004; 4: 40-48
  • 30 Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T, Kastrati A, Schomig A, Schomig E. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501
  • 31 Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, Ball SE. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 2004; 32: 1201-1208
  • 32 Mullangi R, Srinivas NR. Clopidogrel: review of bioanalytical methods, pharmacokinetics/pharmacodynamics, and update on recent trends in drug-drug interaction studies. Biomed Chromatogr 2009; 23: 26-41
  • 33 Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005; 45: 1157-1164