Linked Life Data

14617693

Source:http://linkedlifedata.com/resource/pubmed/id/14617693

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2004-2-26
pubmed:abstractText
Hematopoietic stem cell transplantation patients conditioned with cyclophosphamide (CY) and total body irradiation have substantially greater risk of nonrelapse mortality when plasma area under the concentration-time curve (AUC) of O-carboxyethylcyclophosphoramide mustard (CEPM) is high. The discovery was paradoxical because CEPM is a nontoxic elimination route of the protoxic CY metabolite hydroxycyclophosphamide (HCY). CY was administered to Wistar and TR- rats (a Wistar strain lacking functional ABCC2) at doses of 100 and 200 mg/kg CY, respectively. After either dose, Wistar rats excreted 4-glutathionylcyclophosphamide (GSCY) abundantly in bile; GSCY was absent from bile of TR- rats. Liver AUC(GSCY) was 2- to 2.5-fold greater in TR- than Wistar rats after 100 and 200 mg/kg CY, respectively. Liver AUC(HCY) was 24-46% greater in TR- rats than in Wistar rats after the respective CY doses. Plasma AUC(CEPM) of TR- rats was approximately twice that of Wistar rats after 100 mg/kg, but did not differ between the two strains after 200 mg/kg. Conversely, plasma AUC(HCY) was not different after 100 mg/kg CY, but was 40% greater in TR- rats after 200 mg/kg. The dose dependence of plasma AUC(CEPM) and AUC(HCY) was explained by the concentrations of HCY attained and the in vitro K(m) of aldehyde dehydrogenase and inhibition of aldehyde dehydrogense in TR- rats. We conclude that GSCY is a substrate of ABCC2, and plasma AUC(CEPM) functions as a reporter of liver exposure to HCY and toxins formed from it when HCY concentration is below the K(m) of aldehyde dehydrogenase and the activity is not compromised.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
308
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1204-12
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
ABCC2-mediated biliary transport of 4-glutathionylcyclophosphamide and its contribution to elimination of 4-hydroxycyclophosphamide in rat.
pubmed:affiliation
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't