Skip to main content

Advertisement

Log in

Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the β1 adrenoceptor blocker talinolol.

Methods

The study was conducted in a self-controlled, two-period experiment with a randomized, open-labeled design, using 12 healthy volunteers and a wash out period of 1 week between the administration of a single oral dose of 50 mg talinolol and the concomitant administration of curcumin (300 mg day−1 for 6 days) and a single oral dose of 50 mg talinolol on the seventh day. Concentrations of talinolol were measured in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles, all pharmacokinetic parameters were calculated using DAS (ver. 2.0) software, and comparisons of mean values were analyzed by the Wilcoxon signed rank test. Differences were considered to be significant at p < 0.05 (two-sided test).

Results

The consumption of curcumin for 6 days reduced the area under the curve (AUC) from predose to infinity (\( {\text{AUC}}_{{{\text{0}} - \infty }} \)) of talinolol from 1860.0 ± 377.9 to 1246.0 ± 328.2 ng.h mL−1, the highest observed concentration values (Cmax) were significantly decreased from 147.8 ± 63.8 to 106.4 ± 39.9 ng mL−1, and the CL/F was increased from 27.9 ± 5.5 to 43.1 ± 13.4 L.h−1 (p < 0.05). There was no significant difference in sampling time for Cmax (tmax) and elimination half-life (t1/2) values between the two periods (p > 0.05). The interindividual variability in AUC0–60 and Cmax of talinolol was comparable in two study periods; the coefficient of variance (CV) of AUC0–60 and Cmax was 26 and 40% after curcumin versus 21 and 43% after talinolol alone, respectively.

Conclusion

We suggest that the reduced bioavailability of talinolol is most probably due to the low intraluminal curcumin concentration, or possibly due to the upregulation of further ATP-binding cassette transporters, such as MRP2, in different tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Campeanu A (2001) The cardiac insufficiency talinolol study (CITAS) study design. Eur J Heart Fail 3:377–380

    Article  PubMed  CAS  Google Scholar 

  2. Assmann I (1995) The actions of talinolol, a beta 1-selective beta blocker, in cardiac arrhythmia and acute myocardial infarction. Curr Med Res Opin 13:325–342

    Article  PubMed  CAS  Google Scholar 

  3. Maurer HH, Tenberken O, Kratzsch C (2004) Screening for library-assisted identification and fully validated quantification of 22 beta-blockers in blood plasma by liquid chromatography-mass spectrometry with atmospheric pressure chemical ionization. J Chromatogr A 1058:169–181

    Article  PubMed  CAS  Google Scholar 

  4. Weigmann I, Terhaag B (1995) Cordanum on target: a beta-blocker time tested and up-to date. Pharmedicum 3:216–220

    Google Scholar 

  5. Campeanu A, Olinescu R, Vasile M (1999) Effects of talinolol, a cardioselective betablocker on the oxidative stress in the cigarette smokers. Cardiovasc Drugs Ther 13:68–71

    Google Scholar 

  6. Campeanu A, Olinescu R, Vasile M (1999) Effects of talinolol, aβ1-selective betablocker on the oxidative stress in post unstable angina. Cardiovasc Drugs Ther 13:19–23

    Google Scholar 

  7. Beate T, Oertel R, Richter K et al (1995) Disposition and bioavailability of theβ1-adrenoceptor antagonist talinolol in man. Biopharm Drug Dispos 16:403–414

    Article  Google Scholar 

  8. Gramatte T, Oertel R, Terhaag B (1996) Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans. Clin Pharmacol Ther 59:541–549

    Article  PubMed  CAS  Google Scholar 

  9. Krueger M, Achenbach H, Terhaag B (2001) Pharmacokinetics of oral talinolol following a single dose and during steady state in patients with chronic renal failure and healthy volunteers. Int J Clin Pharm Ther 39:61–66

    CAS  Google Scholar 

  10. Ulrike W, Hildegard SL, Ernst M (1996) Evidence for intestinal secretion as an additional clearance pathway of talinolol enatiomers: concentration- and dose-dependent absorption in vitro and in vivo. Pharm Res 13:514–522

    Article  Google Scholar 

  11. Werner S, Karen L, Georg E (2003) Variability of intestinal expression of p-glycoprotein in healthy volunteers as described by absorption of talinolol from four bioequivalent tablets. J Pharm Sci 92:560–566

    Article  CAS  Google Scholar 

  12. Schwarz UI, Gramatte T, Krappweis J (2000) P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans. Int J Clin Pharm Ther 38:161–167

    CAS  Google Scholar 

  13. Spahn-Langguth H, Langguth P (2001) Grapefruit juice enhances intestinal absorption of the P-glycoprotein substrate talinolol. Eur J Pharm Sci 12:361–367

    Article  PubMed  CAS  Google Scholar 

  14. Cascorbi I (2006) Role of pharmocogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 112:457–473

    Google Scholar 

  15. Sikic BL (1999) Modulation of multidrug resistance: a paradigm for translational clinical research. Oncology 3:183–187

    Google Scholar 

  16. Sharom FJ, Yu X, Lu P et al. (1999) Interaction of the p-glycoprotein multidrug transporter (MDR1) with high affinity peptide chemosensitizers in the isolated membranes, reconstituted systems and intact cells. Biochem Pharmacol 58:571–586

    Article  PubMed  CAS  Google Scholar 

  17. Motterlini R, Foresti R, Bassi R et al. (2000) Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic Biol Med 28:1303–1312

    Article  PubMed  CAS  Google Scholar 

  18. May LA, Tourkin E, Hoffman SR et al. (2005) Detection and quantitation of curcumin in mouse lung cell cultures by matrix-assisted laser desorption ionization time of flight mass spectrometry. Anal Biochem 337:62–69

    Article  PubMed  CAS  Google Scholar 

  19. Shao ZM, Shen ZZ, Liu CH et al. (2002) Curcumin exerts multiple suppressive effects on human breast carcinoma cells. Int J Cancer 98:234–240

    Article  PubMed  CAS  Google Scholar 

  20. Anto RJ, Mukhopadhyaya A, Denning K, Aggarwal B (2002) Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 23:143–150

    Article  PubMed  CAS  Google Scholar 

  21. Rao CV, Rivenson A, Simi B et al. (1995) Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 55:259–266

    PubMed  CAS  Google Scholar 

  22. Huang MT, Lou YR, Ma W et al. (1994) Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res 54:5841–5847

    PubMed  CAS  Google Scholar 

  23. Shukla Y, Arora A, Taneja P (2002) Antimutagenic potential of curcumin on chromosomal aberrations in Wistar rats. Mutat Res 515:197–202

    PubMed  CAS  Google Scholar 

  24. Ikezaki S, Nishikawa A, Furukawa F et al. (2001) Chemopreventive effects of curcumin on glandular stomach carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine and sodium chloride in rats. Anti-Cancer Res 21:3407–3411

    CAS  Google Scholar 

  25. Sharma RA, Ireson CR, Verschoyle et al. (2001) Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. Clin Cancer Res 7:1542–1548

    Google Scholar 

  26. Ireson C, Orr S, Jones DL, Verschoyle R et al. (2001) Characterization of metabolites of the chemopreventive agent curcumin in humans and rat hepatocytes and in rat plasma and evaluation of their ability to inhibit cyclooxygenase-2 expression. Cancer Res 61:1058–1064

    PubMed  CAS  Google Scholar 

  27. Holder GM, Plummer JL, Ryan AJ (1978) The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. Xenobiotica 8:761–768

    Article  PubMed  CAS  Google Scholar 

  28. Wahlstrom B, Blennow G (1978) A study on the fate of curcumin in the rat. Acta Pharm Toxicol 43:86–92

    CAS  Google Scholar 

  29. Cheng AL, Lin JK, Hsu MM et al. (1998) Phase I chemoprevention clinical trial of curcumin. Proc Am Soc Clin Oncol 17:558a

    Google Scholar 

  30. Sharma RA, McLelland HR, Hill KA et al. (2001) Pharmacodynamic and pharmacokinetic study of oral curcuma extract in patients with colorectal cancer. Clin Cancer Res 7:1894–1900

    PubMed  CAS  Google Scholar 

  31. Limtrakul P, Jorearware W, Anuchapreeda S (1998) The effects of curcumin on the proliferation of cancer cell lines. Chiang Mai Med Bull 38:55–61

    Google Scholar 

  32. Mehta K, Pantazis P, McQueen T, Aggarwal BB (1997) Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines. Anti-Cancer Drug 8:470–481

    Article  CAS  Google Scholar 

  33. Songyot A, Pranee L, Melissa MS (2002) Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochem Pharmacol 64:573–582

    Article  Google Scholar 

  34. Limtrakul P, Anuchapreeda S, Buddhasukh D (2004) Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC Cancer 4:13–18

    Article  PubMed  Google Scholar 

  35. Limtrakul P, Anuchapreeda S, Lipigorngoson S, Dunn FW (2001) Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin. BMC Cancer 1:1–7

    Article  PubMed  CAS  Google Scholar 

  36. Rao CV, Rivenson A, Simi B, Reddy BS (1995) Chemoprevention of colon cancer by dietary curcumin. Ann NY Acad Sci 768:201–204

    Article  PubMed  CAS  Google Scholar 

  37. Limtrakul P, Lipigorngoson S, Namwong O, Apisariyakul A, Dunn FW (1997) Inhibitory effect of dietary curcumin on skin carcinogenesis in mice. Cancer Lett 116:197–203

    Article  PubMed  CAS  Google Scholar 

  38. Werner W, Annika B, Thomas G (2005) The talinolol double-peak phenomenon is likely caused by presystemic processing after uptake from gut lumen. Pharm Res 22:728–735

    Article  CAS  Google Scholar 

  39. Westphal K, Weinbrenner A, Giessmann T (2000) Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clin Pharmacol Ther 68:345–355

    Article  PubMed  CAS  Google Scholar 

  40. Oertel R, Richter K, Gramatte T (1998) Determination of drugs in biological fluids by high-performance liquid chromatography with on-line sample processing. J Chromatogr A 797:203–209

    Article  PubMed  CAS  Google Scholar 

  41. Terhaag B, Gramatte T, Richter K (1989) The biliary elimination of the selective beta-receptor blocking drug talinolol in man. Int J Clin Pharmacol Ther Toxicol 27:170–172

    PubMed  CAS  Google Scholar 

  42. Lennernas, H, Regardh CG (1993) Evidence for an interaction between the beta-blocker pafenolol and bile salts in the intestinal lumen of the rat leading to dose-dependent oral absorption and double peaks in the plasma concentration-time profile. Pharm Res 10:879–883

    Article  PubMed  CAS  Google Scholar 

  43. Barnwell SG, Laudanski T, Dwyer M (1993) Reduced bioavailability of atenolol in man: the role of bile acids. Int J Pharm 89:245–250

    Article  CAS  Google Scholar 

  44. Yao H-M, Chiou WL (2006) The complexity of intestinal absorption and exsorption of digoxin in rats. Int J Pharm 322:79–86

    Article  PubMed  CAS  Google Scholar 

  45. Schwarz UI, Gramatte T, Krappweis J (2000) P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans. Int J Clin Pharmacol Ther 38:161–167

    PubMed  CAS  Google Scholar 

  46. Schwarz UI, Gramatte T, Krappweis J (1999) Unexpected effect of verapamil on oral bioavailability of the beta-blocker talinolol in humans. Clin Pharmacol Ther 65:283–290

    Article  PubMed  CAS  Google Scholar 

  47. Budihna MV, Strojan P (1993) Ca2+ channel antagonists inhibit the intestinal absorption of digoxin in the guinea-pig. Eur J Pharmacol 230:301–305

    Article  PubMed  CAS  Google Scholar 

  48. Su SF, Huang JD (1996) Inhibition of the intestinal digoxin absorption and exsorption by quinidine. Drug Metab Dispos 24:142–147

    PubMed  CAS  Google Scholar 

  49. Cvetkovic M, Leake B, Fromm MF (1999) OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27:866–871

    PubMed  CAS  Google Scholar 

  50. Spahn-langguth H, Baktir G, Radschuweit A (1998) P-glycoprotein transporters and the gastrointestinal tract: evaluation of thepotential in vivo relevance of in vitro data employing talinolol as model compound. Int J Clin Pharmacol Ther 36:16–24

    PubMed  CAS  Google Scholar 

  51. Asai A, Miyazawa T (2000) Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sci 67:2785–2793

    Article  PubMed  CAS  Google Scholar 

  52. Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, Lin JK (1997) Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal 15:1867–1876

    Article  PubMed  CAS  Google Scholar 

  53. Srinivas RV, Middlemas D, Flynn P (1998) Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother 42:3157–3162

    PubMed  CAS  Google Scholar 

  54. Gutmann H, Fricker G, Drewe J (1999) nteractions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol 56:383–389

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors are very grateful to Cordanum Arzneimittelwerk Dresden GmbH (Dresden, Germany), for generously providing the talinolol reference standard and tablet formulations. The authors are sincerely thankful to Dr. Fischer Claudia for his generous help in mailing the package of talinolol reference and tablet preparation. Professor Yang Li-Ying is also appreciated for her help on the present subject.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peng Wen-Xing.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Juan, H., Terhaag, B., Cong, Z. et al. Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers. Eur J Clin Pharmacol 63, 663–668 (2007). https://doi.org/10.1007/s00228-007-0298-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-007-0298-0

Keywords

Navigation