Antitumor alkyl ether lipid edelfosine: tissue distribution and pharmacokinetic behavior in healthy and tumor-bearing immunosuppressed mice.
OBJECTIVE
The present study investigates and compares the dose-dependent pharmacokinetics and oral bioavailability of edelfosine in healthy, immunodeficient, and tumor-bearing immunosuppressed mouse animal models, as well as edelfosine uptake and apoptotic activity in the Z-138 mantle cell lymphoma (MCL) cell line.


METHODS
Biodistribution study of edelfosine was done in both BALB/c and severe combined immune deficiency (SCID) mice, and then the in vivo behavior of the drug after i.v. and oral administration was monitored.


RESULTS
We found that edelfosine is incorporated and induces apoptosis in the Z-138 human mantle cell lymphoma cell line, whereas normal resting peripheral blood human lymphocytes were not affected. In vivo biodistribution studies revealed that accumulation of edelfosine in the tumor of a MCL-bearing mouse animal model was considerably higher (P < 0.01) than in the other organs analyzed. Besides, no statistical differences were observed between the pharmacokinetic parameters of BALB/c and SCID mice. Edelfosine presented slow elimination and high distribution to tissues. Bioavailability for a single oral dose of edelfosine was <10%, but a multiple-dose oral administration increased this value up to 64%.


CONCLUSIONS
Our results show that edelfosine is widely scattered across different organs, but it is preferentially internalized by the tumor both in vitro and in vivo. Our data, together with the apoptotic action of the drug on cancer cells, support a rather selective action of edelfosine in cancer treatment, and that multiple oral administration is required to increase oral bioavailability.
Estella-Hermoso de Mendoza
Ander
A
Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, University of Navarra, Pamplona, Spain.
Campanero
Miguel A
MA
de la Iglesia-Vicente
Janis
J
Gajate
Consuelo
C
Mollinedo
Faustino
F
Blanco-Prieto
María J
MJ
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D008214:Lymphocytes / Q000378:metabolism*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010742:Phospholipid Ethers / Q000378:metabolism* / Q000627:therapeutic use; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D010742:Phospholipid Ethers; C026659:edelfosine