The Pharmacokinetics of Chelerythrine Solution and Chelerythrine Liposomes after Oral Administration to Rats

Abstract

Chelerythrine is a quaternary benzo[c]phenanthridine alkaloid which has many potent pharmacological effects and can dissolve well in water; dihydrochelerythrine has recently been identified as a chelerythrine metabolite in rat. Most methods of preparation of liposomes suffer from the drawback of poor incorporation of water-soluble drugs. The emulsion/solvent evaporation method is a relatively simple and efficient way to prepare liposomes loaded with hydrophilic drugs. The aim of this study was therefore to find a suitable formulation to enhance the incorporation of chelerythrine into liposomes by the emulsion/solvent evaporation method and so improve the therapeutic efficacy of chelerythrine. Results showed that the chelerythrine-liposome has been successfully prepared by the emulsion/solvent evaporation method: the entrapment efficiency of chelerythrine was higher at 78.6 %, and the drug loadings reached 7.8 %. The relative bioavailability of chelerythrine and its dihydro derivative in liposomes was significantly increased compared with that of the chelerythrine solution. The area under the plasma concentration–time curve values of chelerythrine and dihydrochelerythrine after oral administration of chelerythrine-liposomes were 4.83-fold and 2.02 higher than those obtained with the chelerythrine solution. The half time and peak concentrations of chelerythrine and dihydrochelerythrine were also higher for chelerythrine-liposomes than that for chelerythrine. In contrast, the total body clearance and apparent volume of distribution were lower for chelerythrine-liposomes in comparison to the respective parameters for the chelerythrine solution. It can thus be concluded that incorporation into liposomes prolonged chelerythrine retention within the systemic circulation.

Key words

chelerythrine - liposome - emulsion/solvent evaporation - pharmacokinetics

• References

• 1 The pharmacopoeia of the peopleʼs Republic of China. Part II. Beijing: The Pharmacopoeia Commission of PRC; 2010
• 2 Mazzanti G, Di Sotto A, Franchitto A, Mammola CL, Mariani P, Mastrangelo S, Menniti-Ippolito F, Vitalone A. Chelidonium majus is not hepatotoxic in Wistar rats, in a 4 weeks feeding experiment. J Ethnopharmacol 2009; 126: 518-524
• 3 Niu XF, Zhou P, Li WF, Xu HB. Effects of chelerythrine, a specific inhibitor of cyclooxygenase-2, on acute inflammation in mice. Fitoterapia 2011; 82: 620-625
• 4 Kosina P, Vacek J, Papoušková B, Stiborová M, Stýskala J, Cankař P, Vrublová E, Vostálová J, Simánek V, Ulrichová J. Identification of benzo[c]phenanthridine metabolites in human hepatocytes by liquid chromatography with electrospray ion-trap and quadrupole time-of-flight mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879: 1077-1085
• 5 Vecera R, Klejdus B, Kosina P, Orolin J, Stiborová M, Smrcek S, Vicar J, Dvorák Z, Ulrichová J, Kubán V, Anzenbacher P, Simánek V. Disposition of sanguinarine in the rat. Xenobiotica 2007; 37: 549-558
• 6 Vacek J, Vrublová E, Kubala M, Janovská M, Fojta M, Šimková E, Stýskala J, Skopalová J, Hrbáč J, Ulrichová J. Oxidation of sanguinarine and its dihydro-derivative at a pyrolytic graphite electrode using Ex Situ Voltammetry. Study of the interactions of the alkaloids with DNA. Electroanalysis 2011; 23: 1671-1680
• 7 Vrublova E, Vostalova J, Vecera R, Klejdus B, Stejskal D, Kosina P, Zdarilova A, Svobodova A, Lichnovsky V, Anzenbacher P, Dvorak Z, Vicar J, Simanek V, Ulrichova J. The toxicity and pharmacokinetics of dihydrosanguinarine in rat: A pilot study. Food Chem Toxicol 2008; 46: 2546-2553
• 8 Pison U, Welte T, Giersig DA, Groneberg M. Nanomedicine for respiratory diseases. Eur J Pharmacol 2006; 533: 341-350
• 9 Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4: 145-160
• 10 Chen LC, Wu YH, Liu IH, Ho CL, Lee WC, Chang CH, Lan KL, Ting G, Lee TW, Shien JH. Pharmacokinetics, dosimetry and comparative efficacy of (188)Re-liposome and 5-FU in a CT26-luc lung-metastatic mice model. Nucl Med Biol 2012; 39: 35-43
• 11 Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci 2009; 71: 349-358
• 12 Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev 2001; 47: 165-196
• 13 Li Q, Jia Y, Sun LX, Xu L, Tong L, Shen ZD, Liu YL, Bi KS. High-performance liquid chromatographic determination of isofraxidin in rat plasma. Chromatographia 2006; 63: 249-253
• 14 Liu DF, Jiang SM, Shen H, Qin S, Liu JJ, Zhang Q, Li R, Xu QW. Diclofenac sodium-loaded solid lipid nanoparticles prepared by emulsion/solvent evaporation method. J Nanopart Res 2011; 13: 2375-2386
• 15 Reddy LH, Vivek K, Bakshi N, Murthy RS. Tamoxifen citrate loaded solid lipid nanoparticles (SLN): preparation, characterization, in vitro drug release, and pharmacokinetic evaluation. Pharm Dev Technol 2006; 11: 167-177
• 16 Liu J, Hu W, Chen H, Ni Q, Xu H, Yang X. Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery. Int J Pharm 2007; 328: 191-195
• 17 Zhang X, Lu S, Han J, Sun S, Wang L, Li Y. Preparation, characterization and in vivo distribution of solid lipid nanoparticles loaded with syringopicroside. Pharmazie 2011; 66: 404-407
• 18 China SFDA. Technical guideline on non-clinical pharmacokinetic studies, 2005. Available at. http://www.sfda.com Accessed 2012
• 19 Gao SH, Fan GR, Hong ZY, Yin XP, Yang SL, Wu YT. HPLC determination of polydatin in rat biological matrices: application to pharmacokinetic studies. J Pharm Biomed Anal 2006; 41: 240-245
• 20 Suresh G, Manjunath K, Venkateswarlu V, Satyanarayana V. Preparation, characterization, and in vitro and in vivo evaluation of lovastatin solid lipid nanoparticles. AAPS Pharm Sci Technol 2007; 8: 162-170
• 21 Zhang J, Fan Y, Smith E. Experimental design for the optimization of lipid nanoparticles. J Pharm Sci 2009; 98: 1813-1819
• 22 Anton N, Benoit JP, Saulnier P. Design and production of nanoparticles formulated from nano-emulsion templates-a review. J Control Release 2008; 128: 185-199
• 23 Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS Pharm Sci Technol 2011; 12: 62-76