All Title Author
Keywords Abstract

Molecules  2014 

Pharmacokinetics of BMEDA after Intravenous Administration in Beagle Dogs

DOI: 10.3390/molecules19010538

Keywords: acute toxicity, radiopharmaceutical, BMEDA, 188Re-BMEDA-liposome, pharmacokinetics

Full-Text   Cite this paper   Add to My Lib


The pharmacokinetics of N, N-bis(2-mercapatoethly)- N', N'-diethylenediamine (BMEDA), a molecule that can form a chelate with rhenium-188 ( 188Re) to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles’ plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC 0–t and AUC 0–∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.


[1]  Parkin, D.M.; Bray, F.; Ferlay, J.; Pisani, P. Estimating the world cancer burden: Globocan 2000. Int. J. Cancer 2001, 94, 153–156, doi:10.1002/ijc.1440.
[2]  Larsson, S.C.; Wolk, A. Meat consumption and risk of colorectal cancer: A meta-analysis of prospective studies. Int. J. Cancer 2006, 119, 2657–2664, doi:10.1002/ijc.22170.
[3]  Ting, G.; Chang, C.H.; Wang, H.E. Cancer nanotargeted radiopharmaceuticals for tumor imaging and therapy. Anticancer Res. 2009, 29, 4107–4118.
[4]  Lombardi, L.; Morelli, F.; Cinieri, S.; Santini, D.; Silvestris, N.; Fazio, N.; Orlando, L.; Tonini, G.; Colucci, G.; Maiello, E. Adjuvant colon cancer chemotherapy: Where we are and where we’ll go. Cancer Treat. Rev. 2010, 36, S34–S41, doi:10.1016/S0305-7372(10)70018-9.
[5]  Peer, D.; Karp, J.M.; Hong, S.; Farokhzad, O.C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751–760, doi:10.1038/nnano.2007.387.
[6]  Torchilin, V.P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 2005, 4, 145–160, doi:10.1038/nrd1632.
[7]  Emfietzoglou, D.; Kostarelos, K.; Sgouros, G. An analytic dosimetry study for the use of radionuclide-liposome conjugates in internal radiotherapy. J. Nucl. Med. 2001, 42, 499–504.
[8]  Mitra, A.; Nan, A.; Line, B.R.; Ghandehari, H. Nanocarriers for nuclear imaging and radiotherapy of cancer. Curr. Pharm. Des. 2006, 12, 4729–4749, doi:10.2174/138161206779026317.
[9]  Chang, C.H.; Stabin, M.G.; Chang, Y.J.; Chen, L.C.; Chen, M.H.; Chang, T.J.; Lee, T.W.; Ting, G. Comparative dosimetric evaluation of nanotargeted 188Re-(DXR)-liposome for internal radiotherapy. Cancer Biother. Radiopharm. 2008, 23, 749–758, doi:10.1089/cbr.2008.0489.
[10]  Hamoudeh, M.; Kamleh, M.A.; Diab, R.; Fessi, H. Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer. Adv. Drug Deliv. Rev. 2008, 60, 1329–1346, doi:10.1016/j.addr.2008.04.013.
[11]  Knapp, F.F., Jr.; Beets, A.L.; Guhlke, S.; Zamora, P.O.; Bender, H.; Palmedo, H.; Biersack, H.J. Availability of rhenium-188 from the alumina-based tungsten-188/rhenium-188 generator for preparation of rhenium-188-labeled radiopharmaceuticals for cancer treatment. Anticancer Res. 1997, 17, 1783–1795.
[12]  Chen, L.C.; Chang, C.H.; Yu, C.Y.; Chang, Y.J.; Wu, Y.H.; Lee, W.C.; Yeh, C.H.; Lee, T.W.; Ting, G. Pharmacokinetics, Micro-SPECT/CT imaging and therapeutic efficacy of 188Re-DXR-liposome in C26 colon carcinoma ascites mice model. Nucl. Med. Biol. 2008, 35, 883–893, doi:10.1016/j.nucmedbio.2008.09.005.
[13]  Chen, L.C.; Wu, Y.H.; Liu, I.H.; Ho, C.L.; Lee, W.C.; Chang, C.H.; Lan, K.L.; Ting, G.; Lee, T.W.; Shien, J.H. Pharmacokinetics, dosimetry and comparative efficacy of 188Re-liposome and 5-fu in a CT26-luc lung-metastatic mice model. Nucl. Med. Biol. 2012, 39, 35–43, doi:10.1016/j.nucmedbio.2011.06.010.
[14]  Hsu, C.W.; Chang, Y.J.; Chang, C.H.; Chen, L.C.; Lan, K.L.; Ting, G.; Lee, T.W. Comparative therapeutic efficacy of rhenium-188 radiolabeled-liposome and 5-fluorouracil in LS-174T human colon carcinoma solid tumor xenografts. Cancer Biother. Radiopharm. 2012, 27, 481–489, doi:10.1089/cbr.2011.1158.
[15]  Chang, Y.J.; Hsu, C.W.; Chang, C.H.; Lan, K.L.; Ting, G.; Lee, T.W. Therapeutic efficacy of 188Re-liposome in a C26 murine colon carcinoma solid tumor model. Investig. New Drugs 2013, 31, 801–811, doi:10.1007/s10637-012-9906-7.
[16]  Liu, C.M.; Tsai, C.C.; Yu, C.Y.; Lee, W.C.; Ho, C.L.; Chang, T.J.; Chang, C.H.; Lee, T.W. Extended acute toxicity study of 188Re-liposome in rats. J. Appl. Toxicol. 2013, 33, 886–893, doi:10.1002/jat.2751.
[17]  Bao, A.; Goins, B.; Klipper, R.; Negrete, G.; Mahindaratne, M.; Phillips, W.T. A novel liposome radiolabeling method using 99mTc-“SNS/S” complexes: In vitro and in vivo evaluation. J. Pharm. Sci. 2003, 92, 1893–1904, doi:10.1002/jps.10441.
[18]  Bao, A.; Goins, B.; Klipper, R.; Negrete, G.; Phillips, W.T. 186Re-liposome labeling using 186Re-SNS/S complexes: In vitro stability, imaging, and biodistribution in rats. J. Nucl. Med. 2003, 44, 1992–1999.
[19]  Bao, A.; Goins, B.; Klipper, R.; Negrete, G.; Phillips, W.T. Direct 99mTc labeling of pegylated liposomal doxorubicin (doxil) for pharmacokinetic and non-invasive imaging studies. J. Pharmacol. Exp. Ther. 2004, 308, 419–425.
[20]  Tsai, C.C.; Chang, C.H.; Chen, L.C.; Chang, Y.J.; Lan, K.L.; Wu, Y.H.; Hsu, C.W.; Liu, I.H.; Ho, C.L.; Lee, W.C.; et al. Biodistribution and pharmacokinetics of 188Re-liposomes and their comparative therapeutic efficacy with 5-fluorouracil in C26 colonic peritoneal carcinomatosis mice. Int. J. Nanomed. 2011, 6, 2607–2619.
[21]  Chang, C.H.; Chiu, S.P.; Chiang, T.C.; Lee, T.W. Acute intravenous injection toxicity of BMEDA in mice. Drug Chem. Toxicol. 2011, 34, 20–24, doi:10.3109/01480545.2010.482588.
[22]  Liu, S.Y.; Chang, C.H.; Lee, T.W. Institute of Nuclear Energy Research, Taoyuan, Taiwan. Unpublished work, 2013.
[23]  Lin, J.H. Dose-dependent pharmacokinetics: Experimental observations and theoretical considerations. Biopharm. Drug Dispos. 1994, 15, 1–31, doi:10.1002/bdd.2510150102.
[24]  Shand, D.G.; Rangno, R.E. The disposition of propranolol. I. Elimination during oral absorption in man. Pharmacology 1972, 7, 159–168, doi:10.1159/000136285.
[25]  Walle, T.; Conradi, E.C.; Walle, U.K.; Fagan, T.C.; Gaffney, T.E. The predictable relationship between plasma levels and dose during chronic propranolol therapy. Clin. Pharmacol. Ther. 1978, 24, 668–677.
[26]  Makar, A.B.; Mannering, G.J. Kinetics of ethanol metabolism in the intact rat and monkey. Biochem. Pharmacol. 1970, 19, 2017–2022, doi:10.1016/0006-2952(70)90298-4.
[27]  Levy, G.; Yacobi, A. Letter: Effect of plasma protein binding on elimination of warfarin. J. Pharm. Sci. 1974, 63, 805–806, doi:10.1002/jps.2600630539.
[28]  Schary, W.L.; Rowland, M. Protein binding and hepatic clearance: Studies with tolbutamide, a drug of low intrinsic clearance, in the isolated perfused rat liver preparation. J. Pharmacokinet. Biopharm. 1983, 11, 225–243, doi:10.1007/BF01061866.
[29]  Jusko, W.J.; Gretch, M. Plasma and tissue protein binding of drugs in pharmacokinetics. Drug Metab. Rev. 1976, 5, 43–140, doi:10.3109/03602537608995839.
[30]  Lin, J.H. Species differences in protein binding of diflunisal. Drug Metab. Dispos. 1989, 17, 221–223.
[31]  Levy, G.; Tsuchiya, T.; Amsel, L.P. Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man. Clin. Pharmacol. Ther. 1972, 13, 258–268.
[32]  Perrier, D.; Gibaldi, M. General derivation of the equation for time to reach a certain fraction of steady state. J. Pharm. Sci. 1982, 71, 474–475, doi:10.1002/jps.2600710432.


comments powered by Disqus

Contact Us


微信:OALib Journal