Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine.
OBJECTIVE
Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and total body clearance.


METHODS
Rat livers were implanted with Walker-256 tumors. The tumor-bearing rats received 15 min infusions of amifostine (200 mg/kg) via the portal vein or the femoral vein. WR-1065 concentrations in the blood, liver and tumor were measured at various times.


RESULTS
The WR-1065 tumor portal dosing AUC15-60 was 40% of systemic dosing, and tumor concentrations following portal dosing were one-fifth of that following systemic dosing. The portal dosing WR-1065 liver AUC15-60 was 60% higher than the values for systemic dosing. The liver/tumor concentration ratios of WR-1065 following portal dosing were up to 8-fold higher than the ratio following systemic administration. Unfortunately, systemic exposure to WR-1065 was greater following portal vs systemic amifostine.


CONCLUSIONS
Amifostine may provide increased liver protection and decreased tumor protection from radio- or chemotherapy when administered by the portal vein. However, portal dosing also increases systemic exposure to WR-1065, which is associated with hypotension.
Levi
Micha
M
College of Pharmacy, The University of Michigan, Ann Arbor, Michigan, USA. micha@c255.ucsf.edu
DeRemer
Susan J
SJ
Dou
Chunzhi
C
Ensminger
William D
WD
Smith
David E
DE
D004999:Amifostine / Q000008:administration & dosage* / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002279:Carcinoma 256, Walker / Q000098:blood supply / Q000601:surgery; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D005268:Femoral Vein / Q000187:drug effects; D007262:Infusions, Intravenous; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D008297:Male; D008624:Mercaptoethylamines / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D009368:Neoplasm Transplantation / Q000379:methods; D011169:Portal Vein / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D008624:Mercaptoethylamines; D011355:Prodrugs; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine