Toxicity and disposition of TLC ELL-12 (liposomal antitumor ether lipid) in Sprague-Dawley rats.
TLC ELL-12 is a liposomal formulation of the antineoplastic L-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine [L-ET-18-OCH3 (EL)]. The purpose of these studies was to characterize the toxicity and disposition of [N-methyl-14C] L-ET-18-OCH3 administered as TLC ELL-12. Rats received TLC ELL-12 by i.v. infusion into a tail vein as a single 12.5 or 62.5 mg/kg dose or as five daily doses at 12.5 mg/kg (cumulative dose of 62.5 mg/kg). Whole blood and tissue samples were collected over 24 h, and assayed for total and EL-specific radioactivity. The amounts of radioactivity in urine, bile, injection site and carcass were determined for up to 48 h. TLC ELL-12 was well tolerated in male and female rats in single doses up to 37.5 mg/kg. The minimum lethal dose was 112.5 mg/kg. Doses of 12.5 mg/kg (no observed adverse effects) and 62.5 mg/kg (approximate maximum tolerated dose) were chosen for further study. The pharmacokinetics of EL given as TLC ELL-12 were non-linear with a disproportionate increase in AUC at the higher dose. Daily dosing at 12.5 mg/kg did not result in accumulation in the blood. The highest concentrations of EL at 24 h after dosing were in the spleen and liver. Virtually no radioactivity was recovered in the urine or bile of rats, most remaining in the carcass and injection site (tail). After a 12.5 mg/kg dose of TLC ELL-12, the levels of EL in the blood and most tissues examined were well above the levels that inhibit tumor growth and may therefore be therapeutically active.
Bhamra
Rupinder
R
Elan Pharmaceuticals, Inc, One Research Way, Princeton, NJ 08540, USA.
Bolcsak
Lois E
LE
Roberts
Patricia
P
Stevens
Rachel
R
Cavanaugh
Christopher
C
Swenson
Christine E
CE
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D002247:Carbon Isotopes; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006461:Hemolysis; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D008657:Metabolic Clearance Rate; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D010742:Phospholipid Ethers; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute
D000970:Antineoplastic Agents; D002247:Carbon Isotopes; D008081:Liposomes; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; C026659:edelfosine