Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetics of liposomal curcumin (Lipocurc™) infusion: effect of co-medication in cancer patients and comparison with healthy individuals

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Investigation of the impact of co-medication on the plasma levels of curcumin and tetrahydrocurcumin (THC) in cancer patients and a comparison of the pharmacokinetics of curcumin and plasma levels of THC between cancer patients and healthy individuals following intravenous infusion of Lipocurc™ (liposomal curcumin).

Methods

Correlation analysis was used to determine the impact of co-medication on infusion rate normalized plasma levels of curcumin and THC in cancer patients and to compare the plasma levels of curcumin and THC at different infusion rates between cancer patients and healthy individuals. In vitro hepatocyte and red blood cell distribution experiments were conducted with Lipocurc™ to support clinical findings. Plasma concentration time data were analyzed by the non-compartmental method to determine and compare the pharmacokinetic parameters of curcumin in cancer patients and healthy individuals.

Results

Of 44 co-medications studied, three medications targeting the renin–angiotensin system, Lisinopril, Ramipril, and Valsartan elevated plasma levels of curcumin and THC in three cancer patients infused with Lipocurc™. Cell distribution experiments indicated that the disposition of curcumin in red blood cells may be a target for elevation of the plasma levels of curcumin. Plasma levels of curcumin in cancer patients increased to a greater extent with increased infusion rate compared to healthy individuals. Upon termination of infusion, the elimination phase for curcumin was shorter with a shorter terminal half-life and smaller volume of distribution for curcumin in cancer patients compared to healthy individuals.

Conclusion

Either co-medications or health status, or both, can impact the pharmacokinetics of curcumin infusion (as Lipocurc™) in cancer patients.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Chen AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS et al (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21:2895–2900

    PubMed  Google Scholar 

  3. Dhillon D, Aggarwal BB, Newman RA, Wolfe RA, Kunnumakkara AB, Abbruzzese JL et al (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14:4491–4499

    Article  CAS  Google Scholar 

  4. Li M, Zhang Z, Hill DL, Wang H, Zhang R (2007) Curcumin, a dietary component, has anticancer chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3/mTOR/ETS2 pathway. Cancer Res 67:1988–1996

    Article  CAS  Google Scholar 

  5. Chang Y-F, Chuang H-Y, Hsu C-H, Liu R-S, Gambhir SS, Hwant J-J (2012) Immunomodulation of curcumin on adoptive therapy with t cell functional imaging in mice. Cancer Prev Res 5:444–452

    Article  CAS  Google Scholar 

  6. Bhattacharyya S, Hossain DMS, Mohanty S, Senj GS, Chattopadhyay S, Banerjee S. Chankraborty J, Das K, Dptendra S, Das T, Gaurisankar S (2010) Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cell Mol Immunol 7:6306–6315

    Article  Google Scholar 

  7. Gosh AK, Kay NE, Secreto CR, Shanafelt TD (2009) Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with ECGC. Clin Cancer Res 15:1250–1258

    Article  Google Scholar 

  8. Everett PC, Meyers JA, Makkinje A, Rabbi M, Lerner A (2007) Preclinical assessment of curcumin as a potential therapy for B-CLL. Am J Hematol 82:23–30, 2007

    Article  CAS  Google Scholar 

  9. Garcea G, Jones DLJ, Singh R, Dennison AR, Farmer PN, Sharma RA et al (2004) Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Brit J Cancer 90:1011–1015

    Article  CAS  Google Scholar 

  10. Zhongfa L, Chiu M, Wang J, Chen W, Yen W, Fan-Havard P et al (2012) Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice. Cancer Chemother Pharmacol 69:679–689

    Article  Google Scholar 

  11. Prasad S, Tyagi AK, Aggarwal BB (2014) Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Cancer Res Treat 46:2–18

    Article  CAS  Google Scholar 

  12. Priyadarsini KI (2014) The chemistry of curcumin: from extraction to therapeutic agent. Molecules 19:20091–20112

    Article  Google Scholar 

  13. Wang Y-J, Pan M-H, Cheng A-L, Lin L-L, Ho Y-S, Hsieh C-Y et al (1997) Stability of curcumin in buffer solutions and characterization of its degradation products. J Phamaceut Biomed Anal 15:1867–1976

    Article  CAS  Google Scholar 

  14. Pan MH, Sy L-S, Lin JK (2000) Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages. Biochem Pharmacol 60:1665–1676

    Article  CAS  Google Scholar 

  15. Yang K-Y, Lin L-C, Tseng T-Y, Wang S-C, Tsai T-H (2007) Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC–MS/MS. J Chromatograph B 853:183–189

    Article  CAS  Google Scholar 

  16. Tsai Y-M, Chien C-F, Lin L-C, Tsai T-H (2011) Curcumin and its nano-formulation: the kinetics of tissue distribution and blood–brain barrier penetration. Int J Pharm 416:331–338

    Article  CAS  Google Scholar 

  17. Helson L, Bolger G, Majeed M, Vcelar B, Pucaj K, Matabudul D (2012) Infusion pharmacokinetics of Lipocurc™ (liposomal curcumin) and its metabolite tetrahydrocurcumin in beagle dogs. Anticancer Res 32:4365–4370

    CAS  PubMed  Google Scholar 

  18. Gutierres VO, Campos ML, Aracar CA, Assis RP, Baldan-Cimatti HM, Peccinini RG et al (2015) Curcumin pharmacokinetics and pharmacodynamic evidences in streptozotocin-diabetic rats support the antidiabetic activity to be via metabolites. Evid Based Complement Altern Med. https://doi.org/10.1155/2015/678218

    Article  Google Scholar 

  19. Storka A, Vcelar B, Klickovic U, Gouya G, Weisshaar S, Aschauer S et al (2015) Safety, tolerability and pharmacokinetics of liposomal curcumin (Lipocurc™) in healthy humans. Int J Clin Pharmacol Ther 53:54–65

    Article  CAS  Google Scholar 

  20. Bolger GT, Licollari A, Tan A, Griel R, Vcelar B, Majeed M et al (2017) Distribution and metabolism of Lipocurc™ (Liposomal curcumin) in dog and human blood cells: species selectivity and pharmacokinetic relevance. Anticancer Res 37:3483–3492

    CAS  PubMed  Google Scholar 

  21. Golombick T, Diamon TH, Manoharan A, Ramakrishna R (2015) The effects of curcumin (as Meriva) on absolute lymphocyte count (ALC), NK cells and T cell populations in patients with stage 0/1 chronic lymphocytic leukemia. J Cancer Ther 6:566–571

    Article  CAS  Google Scholar 

  22. Rajan AP, Mukerjee A, Helson L, Gupta R, Vishwanatha JK (2013) Efficacy of liposomal curcumin in a human pancreatic tumor xenograft model: inhibition of tumor growth and angiogenesis. Anticancer Res 33:3603–3609

    Google Scholar 

  23. Greil R, Greil-Ressler S, Weiss L, Schönlieb C, Magnes T, Radl B et al (2018) A phase 1 dose escalation study on the safety, tolerability and activity of liposomal curcumin (Lipocurc™) in patients with locally advanced or metastatic cancer. Cancer Chemother Pharmacol 82:695–706

    Article  CAS  Google Scholar 

  24. Tan A, Wu Y, Wong M, Licollari A, Bolger G, Fanaras J et al (2016) Use of basic mobile phase to improve chromatography and boost sensitivity for quantifying tetrahydrocurcumin in human plasma by LC–MS/MS. J Chromatograph B 1028:86–93

    Article  CAS  Google Scholar 

  25. Huang Z, Li H, Zhang Q, Tan X, Lu F, Liu H et al (2015) Characterization of preclinical in vitro and in vivo pharmacokinetic properties for KBP-7018, a new tyrosine kinase inhibitor candidate for treatment of idiopathic pulmonary fibrosis. Drug Des Dev Ther 9:4319–4328

    CAS  Google Scholar 

  26. Oostendorp RL, van de Steeg E, van der Kruijssen CMM, Beijnen JH, Kenworthy KE, Schinkel AH et al (2009) Organic anion-transporting polypeptide 1B1 mediates transport of bimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors. Drug Metab Dispos 37:917–923

    Article  CAS  Google Scholar 

  27. Niles AT, Hofmann U, Resch C, Schaeffeler E, Rius M, Schwab M (2011) Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs). PLoS One 6(7):e22163

    Article  Google Scholar 

  28. Zhou X, Zhang F, Chen C, Guo Z, Liu J, Yu J et al (2016) Impact of curcumin on the pharmacokinetics of rousuvastatin in rats and dogs based on the conjugated metabolites. Xenobiotica 47:267–275

    Article  Google Scholar 

  29. Cossum PA (1988) Role of the red blood cell in drug metabolism. Biopharm Drug Dispos 9:321–336

    Article  CAS  Google Scholar 

  30. Pratt MC, Lewis-Barned NJ, Walker RJ, Bailey RR, Shand BI, Livesey J (1992) Effects of angiotensin converting enzyme inhibitors on erythropoietin concentrations in health volunteers. Br J Clin Pharm 34:363–365

    Article  CAS  Google Scholar 

  31. Mohanram A, Zhang Z, Shahinfar S, Lyle PA, Toto RD (2008) The effect of losartan on hemoglobin concentration and renal outcome in diabetic nephropathy of type 2 diabetes. Kidney Int 73:630–636

    Article  CAS  Google Scholar 

  32. Kim Y-C, Mungunsukh O, McCart EA, Roehrich PJ, Yee DK, Day RM (2014) Mechanism of erythropoietin regulation by angiotensin II. Mol Pharmacol 85:898–908

    Article  Google Scholar 

  33. Kato H, Ishida J, Matsusaka T, Ishimaru T, Tanimoto K, Sugiyama F (2015) Erythropoiesis and blood pressure are regulated via AT1 receptor by distinctive pathways. PLoS One 10(6):e0129484

    Article  Google Scholar 

  34. Sánchez RA, Giménez MI, Gilbert GH, Giannone C, Marco EJ, Ramirez AJ (1991) Recovery of erythrocyte Na+–K+–Cl– cotransport activity by enalapril. Hypertension 17:331–334

    Article  Google Scholar 

  35. Herlitz H, Dahlöf B, Jonsson O, Hansson L (1994) Relationship between change in erythrocyte sodium and antihypertensive response to enalapril. J Hum Hypertens 8:837–841

    CAS  PubMed  Google Scholar 

  36. Sánchez RA, Giménez MI, Miglorini M, Giannone C, Ramirez AJ, Weder AB (1997) Erythrocyte sodium-lithium countertransport in non modulating offspring and essential hypertensive individuals. Response Enalapril Hypertens 30:99–105

    Article  Google Scholar 

  37. Storka A, Vcelar B, Klickovic U, Gouya G, Weisshaar S, Aschauer S (2013) Effect of liposomal curcumin on red blood cells in vitro. Anticancer Res 33:3629–3634

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Ms. Lena Nguyen for her careful review of the manuscript.

Funding

This study was entirely funded by SignPath Pharma Inc.

Author information

Authors and Affiliations

  1. Nucro-Technics, 2000 Ellesmere Road, Unit 16, Scarborough, ON, M1H 2W4, Canada

    Gordon T. Bolger, Albert Licollari & Amin Tan

  2. III rd Medical Department, Paracelsus Medical University Salzburg, Salzburg, Austria

    Richard Greil, Sigrun Greil-Ressler, Lukas Weiss, Charlotte Schönlieb, Teresa Magnes & Bianca Radl

  3. Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Salzburg, Austria

    Richard Greil, Sigrun Greil-Ressler, Lukas Weiss, Charlotte Schönlieb, Teresa Magnes & Bianca Radl

  4. Cancer Cluster Salzburg, Salzburg, Austria

    Richard Greil

  5. Polymun Scientific Immunbiologische Forschung GmbH, Klosterneuburg, Austria

    Brigitta Vcelar

  6. Sabinsa Corporation, East Windsor, NJ, USA

    Muhammed Majeed

  7. SignPath Pharma, Inc, 51 East 82 Street, #1A, New York, NY, 10028, USA

    Peter P. Sordillo

Authors
  1. Gordon T. Bolger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albert Licollari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amin Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Greil
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brigitta Vcelar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sigrun Greil-Ressler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lukas Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Charlotte Schönlieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Teresa Magnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bianca Radl
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Muhammed Majeed
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Peter P. Sordillo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GB and AL were involved in PK analysis, AT was involved in the Bioanalysis and GB wrote the manuscript. For the clinical studies, RG was involved in study design, recruitment and treatment of patients, discussion of safety and efficacy issue of patients with the external safety committee, critical analysis of the data, writing of the paper. SGR, LW, CS, TM and BR were involved in recruiting and treatment of patients. BV was involved in study design, study coordination, and critical analysis of the data MM was involved in critical analysis of the data. MM provided the curcumin for the production of Lipocurc™. PPS was involved in study design, critical analysis of the data and writing of the manuscript. All authors critically read the manuscript.

Corresponding authors

Correspondence to Gordon T. Bolger or Peter P. Sordillo.

Ethics declarations

Conflict of interest

PPS is vice president and chief scientific officer at SignPath Pharma Inc. No potential conflict of interest was disclosed by RG, BV, SGR, LW, CS, TM, BR, MM, GB, AL and AT. Cancer patients enrolled in this study provided written informed consent.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bolger, G.T., Licollari, A., Tan, A. et al. Pharmacokinetics of liposomal curcumin (Lipocurc™) infusion: effect of co-medication in cancer patients and comparison with healthy individuals. Cancer Chemother Pharmacol 83, 265–275 (2019). https://doi.org/10.1007/s00280-018-3730-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-018-3730-5

Keywords

Search

Navigation