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

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Title: Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine.
Authors: Micha Levi, Susan J. DeRemer1, Chunzhi Dou1
Source: Biopharmaceutics & Drug Disposition. Jan2004, Vol. 25 Issue 1, p27-35. 9p.
Subject Terms: *PRODRUGS, *METABOLITES, *ALKALINE phosphatase, *LIVER tumors, *THERAPEUTICS
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. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
Copyright of Biopharmaceutics & Drug Disposition is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Label: Title
  Group: Ti
  Data: Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine.
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  Data: <searchLink fieldCode="AR" term="%22Micha+Levi%22">Micha Levi</searchLink><br /><searchLink fieldCode="AR" term="%22Susan+J%2E+DeRemer%22">Susan J. DeRemer</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Chunzhi+Dou%22">Chunzhi Dou</searchLink><relatesTo>1</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Biopharmaceutics+%26+Drug+Disposition%22">Biopharmaceutics & Drug Disposition</searchLink>. Jan2004, Vol. 25 Issue 1, p27-35. 9p.
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: *<searchLink fieldCode="DE" term="%22PRODRUGS%22">PRODRUGS</searchLink><br />*<searchLink fieldCode="DE" term="%22METABOLITES%22">METABOLITES</searchLink><br />*<searchLink fieldCode="DE" term="%22ALKALINE+phosphatase%22">ALKALINE phosphatase</searchLink><br />*<searchLink fieldCode="DE" term="%22LIVER+tumors%22">LIVER tumors</searchLink><br />*<searchLink fieldCode="DE" term="%22THERAPEUTICS%22">THERAPEUTICS</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Biopharmaceutics & Drug Disposition is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1002/bdd.380
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        Text: English
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        Type: general
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      – SubjectFull: ALKALINE phosphatase
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      – TitleFull: Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine.
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              Text: Jan2004
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