TY - JOUR T1 - ABCC2-Mediated Biliary Transport of 4-Glutathionylcyclophosphamide and Its Contribution to Elimination of 4-Hydroxycyclophosphamide in Rat JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1204 LP - 1212 DO - 10.1124/jpet.103.059105 VL - 308 IS - 3 AU - Ruolun Qiu AU - Thomas F. Kalhorn AU - John T. Slattery Y1 - 2004/03/01 UR - http://jpet.aspetjournals.org/content/308/3/1204.abstract N2 - 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 AUCGSCY was 2- to 2.5-fold greater in TR- than Wistar rats after 100 and 200 mg/kg CY, respectively. Liver AUCHCY was 24-46% greater in TR- rats than in Wistar rats after the respective CY doses. Plasma AUCCEPM 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 AUCHCY was not different after 100 mg/kg CY, but was 40% greater in TR- rats after 200 mg/kg. The dose dependence of plasma AUCCEPM and AUCHCY was explained by the concentrations of HCY attained and the in vitro Km of aldehyde dehydrogenase and inhibition of aldehyde dehydrogense in TR- rats. We conclude that GSCY is a substrate of ABCC2, and plasma AUCCEPM functions as a reporter of liver exposure to HCY and toxins formed from it when HCY concentration is below the Km of aldehyde dehydrogenase and the activity is not compromised. The American Society for Pharmacology and Experimental Therapeutics ER -