Pharmacokinetics and metabolism of a new antitumor semisynthetic ether phospholipid, 14C-labeled plasmanyl-(N-acyl)ethanolamine, in mice bearing sarcoma Mc11.
New natural and semisynthetic antitumor ether phospholipids PNAE and PNAE(s) [plasmanyl-(N-acyl)ethanolamines] and their selective antitumor activity in vivo have been described previously. We are now presenting the pharmacokinetics, in vivo metabolism and distribution of a [14C]PNAE(s) preparation (1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-[U-14C]palmitoyl) ethanolamine in the intact or Mc11-tumor-bearing BDF1 mice. Only partial degradation (about 50%-60%) of [14C]PNAE(s) was observed in vivo 24 h after i.v. administration, as detected by TLC analysis of phospholipids extracted from the blood, liver, tumor and brain of animals. Pharmacokinetic curves of [14C]PNAE(s) and its metabolites were fitted with a two-compartment model (t alpha 1/2 = 2.5 h, t beta 1/2 = 61.6 h). After repeated i.v. doses of [14C]PNAE(s) (administered on days 1, 2, 3, 4, and 5) accumulation of [14C]PNAE(s) and lyso-[14C]PNAE(s) in tumor tissue was detected. High levels of [14C]PNAE(s) were also detected in the liver, lung and spleen of animals. After i.v. administration of [14C]PNAE(s) the ether phospholipid was also detected in the brain tissue. The parmacokinetic data indicate that repeated parenteral doses of PNAE(s) are necessary to attain therapeutic concentrations in tumor tissue. The very high accumulation of [14C]PNAE(s) in the liver of animals after repeated i.v. doses, and the absence of toxic side-effects in vivo indicate a possible clinical therapeutic use of PNAE(s), especially in the treatment of tumor metastases in liver as well as in the prophylaxis of liver metastases after surgical removal of primary tumors.
Kára
J
J
Laboratory of Evolutionary Biology, Czech Academy of Sciences Prague 4.
Zimakova
N I
NI
Serebryakova
E A
EA
Dĕdková
V
V
Zolotaryov
A E
AE
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010714:Phosphatidylethanolamines / Q000378:metabolism* / Q000493:pharmacokinetics*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D010714:Phosphatidylethanolamines; C078193:1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)ethanolamine