Improved pharmacokinetics and reduced toxicity of brucine after encapsulation into stealth liposomes: role of phosphatidylcholine.
OBJECTIVE
Brucine was encapsulated into stealth liposomes using the ammonium sulfate gradient method to improve therapeutic index.


METHODS
Four brucine stealth liposomal formulations were prepared, which were made from different phosphatidylcholines (PCs) with different phase transition temperatures (T(m)). The PCs used were soy phosphatidylcholine (SPC), dipalmitoyl phosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), and distearoyl phosphatidylcholine (DSPC). The stabilities, pharmacokinetics, and toxicities of these liposomal formulations were evaluated and compared.


RESULTS
Size, zeta potential, and entrapment efficiency of brucine-loaded stealth liposomes (BSL) were not influenced by PC composition. In vitro release studies revealed that drug release rate increased with decreased T(m) of PCs, especially with the presence of rat plasma. After intravenous administration, the area under the curve (AUC) values of BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC in plasma were 7.71, 9.24, 53.83, and 56.83-fold as large as that of free brucine, respectively. The LD(50) values of brucine solution, BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC following intravenous injection were 13.17, 37.30, 37.69, 51.18, and 52.86 mg/kg, respectively. It was found in calcein retention experiments that the order of calcein retention in rat plasma was SPC < DPPC << HSPC < DSPC stealth liposomes.


CONCLUSIONS
PC composition could exert significant influence on the stabilities, pharmacokinetics, and toxicities of brucine-loaded stealth liposomes. DSPC or HSPC with T(m) above 50°C should be used to prepare the stealth liposomal formulation for the intravenous delivery of brucine. However, it was found in the present paper that the pharmacokinetics and toxicity of BSL were not influenced by the PC composition when the T(m) of the PC was in the range of -20°C to 41°C.
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China.
Jun
J
Chen
Guo-jun
GJ
Yan
Rong-rong
RR
Hu
Qian-wen
QW
Gu
Ming-lei
ML
Chen
Wei
W
Gu
Zhi-peng
ZP
Chen
Bao-chang
BC
Cai
D000818:Animals; D019540:Area Under Curve; D002463:Cell Membrane Permeability; D002851:Chromatography, High Pressure Liquid; D007928:Lethal Dose 50; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D051379:Mice; D010713:Phosphatidylcholines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013331:Strychnine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D013696:Temperature; D023382:Toxicity Tests, Acute
D008081:Liposomes; D010713:Phosphatidylcholines; C083806:brucine; D013331:Strychnine