QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.059105v1 308/3/1204    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Qiu, R. Articles by Slattery, J. T. Search for Related Content PubMed PubMed Citation Articles by Qiu, R. Articles by Slattery, J. T.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

ABCC2-Mediated Biliary Transport of 4-Glutathionylcyclophosphamide and Its Contribution to Elimination of 4-Hydroxycyclophosphamide in Rat

Department of Pharmaceutics, University of Washington, Seattle, Washington (R.Q., T.F.K., J.T.S.); and Fred Hutchinson Cancer Research Center, Seattle, Washington (T.F.K., J.T.S.)

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.

Address correspondence to: Dr. John T. Slattery, Graduate Studies, Kirkwood Hall 111, Indiana University, Bloomington, IN 47405. E-mail: slattery{at}indiana.edu