Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine.

Abstract

PURPOSE:

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.

• Authors: Micha Levi, Susan J DeRemer, Chunzhi Dou, William D Ensminger, David E Smith
• Journal: Biopharmaceutics & drug disposition (Biopharm Drug Dispos) Vol. 25 Issue 1 Pg. 27-35 (Jan 2004) ISSN: 0142-2782 [Print] England
• PMID: 14716750 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2004 John Wiley & Sons, Ltd.

Chemical References

• Antineoplastic Agents
• Mercaptoethylamines
• Prodrugs
• N-(2-mercaptoethyl)-1,3-diaminopropane
• Amifostine

Topics

• Amifostine (administration & dosage, metabolism, therapeutic use)
• Animals
• Antineoplastic Agents (metabolism, pharmacology, therapeutic use)
• Carcinoma 256, Walker (blood supply, surgery)
• Disease Models, Animal
• Drug Delivery Systems (methods)
• Drug Screening Assays, Antitumor
• Femoral Vein (drug effects)
• Infusions, Intravenous
• Liver Neoplasms, Experimental (drug therapy)
• Male
• Mercaptoethylamines (metabolism, pharmacology, therapeutic use)
• Neoplasm Transplantation (methods)
• Portal Vein (drug effects)
• Prodrugs (administration & dosage, metabolism)
• Rats
• Rats, Sprague-Dawley