Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice1

Abstract

Aim: To study the pharmacokinetics and tissue distribution of 5‐fluorouracil encapsulated by galactosylceramide liposomes (5‐Fu‐GCL) in mice. Methods: The concentration of 5‐fluorouracil (5‐Fu) in serum was detected by high performance liquid chromatography after 5‐Fu‐GCL (80, 40, 20 mg/kg) and free 5‐Fu (40 mg/kg) were injected intravenously into mice. The tissue distribution of 5‐Fu‐GCL (40 mg/kg) and free 5‐Fu (40 mg/kg) was investigated, and concentration‐time profile of the two preparations in the liver were studied. Data were analyzed by 3p97 program. Results: Serum concentration‐time curves of 5‐Fu‐GCL and free 5‐Fu conformed to one compartment model of first order absorption. 5‐Fu‐GCL at 80, 40, and 20 mg/kg had T1/2Ke of 25.8±4.2, 27.3±4.4, and 28.2±5.6 min; C0 of 24.9±4.9, 17.7±3.6, and 11.5±2.7 mg/L; and AUC of 990.0±45.2, 622.5±38.3, and 340.4±25.6 mg·min·L‐1, respectively. In contrast free 5‐Fu at 40 kg/mg had T1/2Ke of 15.8±2.2 min, C0 of 35.8±6.2 mg/L, AUC of 639.0±35.9 mg·min·L‐1. The tissue distribution of 5‐Fu‐GCL in the liver and immune organs was significantly increased, while in heart and kidney it was remarkably decreased. The AUC of 5‐Fu‐GCL in the liver was 3 times higher than that of free 5‐Fu. Conclusion: The pharmacokinetics and tissue distribution of 5‐Fu‐GCL appears to be linear‐related and dose‐dependent, and exhibits sustained‐release and hepatic target characteristics.

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

“…In a single study examining 5-fluorouracil alone, four repeated injections of 150 mg/kg 5-fluorouracil failed to alter maze performance in young female rats (Lee et al 2006), a result in contrast to the present findings. The doses of 75 mg/kg (present study) and 150 mg/kg (Lee et al 2006) 5-fluorouracil in mice and rats, respectively, fall slightly below and slightly above the predicted 100-mg/kg-scaled mouse dose as determined from the typical clinical dose used to treat breast cancer in humans (500 mg/m 2 ) (Gusella et al 2006;Jin et al 2005;Kralovanszky et al 1999;Ooi et al 2001;Peters et al 1993). The findings in the present study underscore the importance of examining a range of relevant preclinical and clinical doses in more than one type of assay to capture the relationship of chemotherapeutic agents to changes in different types of learning and memory behaviors.…”

Formulation and Pharmacokinetics of Thermosensitive Stealth® Liposomes Encapsulating 5-Fluorouracil

“…Thomas et al (17) performed a PK study on non-PEGylated liposomes but did not calculate any PK parameters. Jin et al (46) evaluated the PK of galactosylceramide liposomes encapsulating 5-FU and found a shorter distribution half-life of 28 min and a 3 to 5-fold lower AUC of 38 μmol.h.L −1 . Our TSLs and NTSLs formulations are therefore better in terms of exposure.…”

Drug delivery approaches for the treatment of glioblastoma multiforme

“…However, increased circulation time can be accomplished by designing particles of smaller size or by coating the external membrane with specific ligands or proteins (Laquintana et al 2009). Surface-modified liposomes and nanoparticles have shown great promise in the treatment of brain tumor due to their ability to effectively cross the BBB and deliver therapeutic agents to the brain (Huwyler et al 2008, Jin et al 2005.…”