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

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-OCH3). The purpose of these studies was to evaluate the activity and tissue distribution of L-ET-18-OCH3 when administered i.v. as TLC ELL-12 to rats bearing solid tumors. Growth-inhibitory activity of L-ET-18-OCH3 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-OCH3 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-OCH3 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 μM (about 30 μg/ml). Tumor growth was significantly inhibited in ELL-12-treated rats versus controls. After a single dose, whole blood L-ET-18-OCH3 concentrations declined in a multiphasic fashion with Cmax and terminal half-life values of approximately 91.1 μg L-ET-18-OCH3/ml and 13.1 h, respectively. Tumor L-ET-18-OCH3 levels increased through the first 16–24 h post-dosing to about 23 μg/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-OCH3 from the circulation into tissues with highest concentrations in spleen, liver, lungs, kidneys and gastrointestinal tract. L-ET-18-OCH3 as TLC ELL-12 shows both in vitro and in vivo activity against the MNU tumor line. When i.v. administered, L-ET-18-OCH3 from ELL-12 is well distributed and slowly eliminated by metabolism in tissues.