A novel liposomal formulation of flavopiridol.
Flavopiridol has shown promising activities in hematologic and solid tumor models, as well as in clinical trials in chronic lymphocytic leukemia patients. Flavopiridol has relatively low solubility and high plasma protein-binding. To address these issues and to provide an alternative strategy to achieve clinical efficacy, we encapsulated flavopiridol into a liposomal carrier and characterized its physicochemical and pharmacokinetic properties. The liposomes, comprising hydrogenated soy phosphatidylcholine (HSPC), cholesterol and poly (ethylene glycol) 2000-distearoyl phosphatidylethanolamine (PEG-DSPE), were prepared by polycarbonate membrane extrusion and then loaded with flavopiridol by a pH-gradient driven remote loading procedure. The liposomes had a mean diameter of 120.7 nm and a flavopiridol entrapment efficiency of 70.4%. Pharmacokinetic study in mice after i.v. bolus injection showed that the liposomal flavopiridol had an increased elimination phase half-life (T((1/2)beta), 339.7 min vs. 57.0 min), decreased clearance (CL, 0.012 L/min vs. 0.036 L/min), and increased area under the plasma concentration-time curve (AUC, 10.8 min micromol/L vs. 3.4 min micromol/L) compared to the free drug. This indicates a significant and potentially beneficial change in flavopiridol pharmacokinetics for the liposomal formulation. Further preclinical studies are warranted to define the toxicity and therapeutic efficacy of this novel formulation.
Yang
Xiaojuan
X
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Zhao
Xiaobin
X
Phelps
Mitch A
MA
Piao
Longzhu
L
Rozewski
Darlene M
DM
Liu
Qing
Q
Lee
L James
LJ
Marcucci
Guido
G
Grever
Michael R
MR
Byrd
John C
JC
Dalton
James T
JT
Lee
Robert J
RJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004337:Drug Carriers / Q000737:chemistry*; D005419:Flavonoids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D008813:Mice, Inbred ICR; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011076:Polycarboxylate Cement / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D013025:Glycine max / Q000737:chemistry
D000970:Antineoplastic Agents; D004337:Drug Carriers; D005419:Flavonoids; D008081:Liposomes; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010880:Piperidines; D011076:Polycarboxylate Cement; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; C005506:polycarbonate; D011092:Polyethylene Glycols; C077990:alvocidib
Leuk Lymphoma. 2002 Apr;43(4):793-7
12153166
Ann Oncol. 2003 Aug;14(8):1270-3
12881391
J Clin Oncol. 2002 Oct 1;20(19):4074-82
12351605
Oncologist. 2002;7  Suppl 3:12-9
12165651
Anticancer Drugs. 2005 Aug;16(7):691-707
16027517
Clin Cancer Res. 2001 Jun;7(6):1590-9
11410495
J Pharm Sci. 1999 Sep;88(9):945-7
10479359
Blood. 2007 Jan 15;109(2):399-404
17003373
PDA J Pharm Sci Technol. 1996 Nov-Dec;50(6):356-9
9038080
J Clin Oncol. 1998 Sep;16(9):2986-99
9738567
Clin Cancer Res. 2004 Feb 1;10(3):924-8
14871968
Leukemia. 2001 Jan;15(1):1-9
11243375
Clin Cancer Res. 2005 Jun 1;11(11):4176-81
15930354
Ann Pharmacother. 2002 May;36(5):905-11
11978170
Crit Rev Oncol Hematol. 2001 May;38(2):139-70
11311660
Invest New Drugs. 2004 Aug;22(3):315-22
15122079
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Jun 1;868(1-2):110-5
18490204
Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S84-95
14508085
Leuk Res. 2005 Nov;29(11):1253-7
15916806