title: 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.
authors.affiliation: Elan Pharmaceuticals, Inc., Princeton, NJ 08540, USA.
authors.forename: Rupinder
authors.initials: R
authors.lastname: Bhamra
authors.forename: Lois E
authors.initials: LE
authors.lastname: Bolcsak
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.forename: James
authors.initials: J
authors.lastname: Schupsky
authors.forename: Patricia
authors.initials: P
authors.lastname: Roberts
authors.forename: Rachel
authors.initials: R
authors.lastname: Stevens
authors.forename: Christopher
authors.initials: C
authors.lastname: Cavanaugh
authors.forename: Christine E
authors.initials: CE
authors.lastname: Swenson
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D008081:Liposomes; D008657:Metabolic Clearance Rate; D008770:Methylnitrosourea / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010742:Phospholipid Ethers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D008081:Liposomes; D010742:Phospholipid Ethers; C026659:edelfosine; D008770:Methylnitrosourea