Activity, pharmacokinetics and tissue distribution of TLC ELL-12 (liposomal antitumor ether lipid) in rats with transplantable, s.c. methylnitrosourea-induced tumors

Abstract

TLC ELL-12 is a liposomal formulation of the novel antineoplastic compound 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (L-ET-18-OCH(3)). The purpose of these studies was to evaluate the activity and tissue distribution of L-ET-18-OCH(3) when administered i.v. as TLC ELL-12 to rats bearing solid tumors. Growth-inhibitory activity of L-ET-18-OCH(3) and TLC ELL-12 against methylnitrosourea (MNU)-induced tumors grown in vitro was evaluated. Female Buffalo rats were injected s.c. with transplantable MNU-induced tumor cells. Four days later, animals were treated i.v. with L-ET-18-OCH(3) administered as TLC ELL-12 once daily for 5 consecutive days. Another group of MNU-tumor bearing rats was given a single 12.5 mg/kg dose of TLC ELL-12 containing [14C]L-ET-18-OCH(3) by i.v. injection into a tail vein. The 50% growth inhibitory concentration for TLC ELL-12 against MNU tumor cells in vitro was 63 microM (about 30 microg/ml). Tumor growth was significantly inhibited in ELL-12-treated rats versus controls. After a single dose, whole blood L-ET-18-OCH(3) concentrations declined in a multiphasic fashion with C(max) and terminal half-life values of approximately 91.1 microg L-ET-18-OCH(3)/ml and 13.1 h, respectively. Tumor L-ET-18-OCH(3) levels increased through the first 16-24 h post-dosing to about 23 microg/g and remained elevated at the terminal time point with little evidence of metabolism. Concentration-time profiles for selected tissues indicate rapid distribution of L-ET-18-OCH(3) from the circulation into tissues with highest concentrations in spleen, liver, lungs, kidneys and gastrointestinal tract. L-ET-18-OCH(3) as TLC ELL-12 shows both in vitro and in vivo activity against the MNU tumor line. When i.v. administered, L-ET-18-OCH(3) from ELL-12 is well distributed and slowly eliminated by metabolism in tissues.

Immunomodulatory effects of the ether phospholipid edelfosine in experimental autoimmune encephalomyelitis

“…One curious observation is the increase of neutrophils in the CNS of mice receiving 10 mg/kg edelfosine. While we can only speculate on the causes of this finding, edelfosine crosses the BBB (Arnold et al, 1978;Bhamra et al, 2003;Estella-Hermoso de Mendoza et al, 2009). Drug concentrations that are achieved by administration of 10 mg/kg edelfosine treatment may be sufficient to induce activation in neutrophils.…”

“…Additionally, dose rates were limited by edelfosine treatment only every other day. Interestingly, pharmacokinetic studies in rats reported a rapid uptake and distribution of a liposomal formulation of an edelfosine L-isomer into tissues (time to reach highest concentrations: 0.25 to 8 h, half-lives were 13.1 h in blood and 14 h in spleens) (Bhamra et al, 2003). Furthermore, approximately 96% of edelfosine was absorbed in the first 24 hours after oral treatment of rats (Kötting et al, 1992).…”

Complete Inhibition of Extranodal Dissemination of Lymphoma by Edelfosine-Loaded Lipid Nanoparticles

“…Among the different lipid-made colloidal carriers, edelfosine was incorporated into liposomes [6] and lipid nanoparticles (LN) made of biocompatible lipids [7]. The liposomal formulation was able to prevent the hemolytic toxicity of the drug, but the main inconvenience found was its rapid clearance from plasma.…”

Comparative study of A HPLC–MS assay versus an UHPLC–MS/MS for anti-tumoral alkyl lysophospholipid edelfosine determination in both biological samples and in lipid nanoparticulate systems

“…Several analytical procedures have been reported for the quantitation of edelfosine in biological fluid matrices. High performance liquid chromatography assays with radiochemical detection were initially employed for the quantitation of radiolabeled edelfosine in early distribution preclinical studies [9]. However, measurement of total radioactivity does not reflect the real pharmacokinetic behavior or the tissue distribution of the parent drug edelfosine since the radiolabel may be included in some metabolites.…”