Multidrug resistance (MDR) remains a major obstacle in the treatment of human
cancers. The recently discovered
breast cancer resistance
protein (BCRP/ABCG2) has been found to be an important mediator of chemotherapeutic MDR.
Fumitremorgin C (
FTC) is a selective and potent inhibitor of BCRP that completely inhibits and reverses BCRP-mediated resistance at micromolar concentrations. We report a study of the pharmacokinetics and tissue distribution of
FTC when administered intravenously (IV) at a dose of 25 mg/kg to female SCID mice bearing the BCRP-overexpressing human ovarian xenograft Igrov1/T8
tumors. Plasma pharmacokinetics and tissue distribution of
FTC in various organs and tissues were studied. In addition, the effect of
FTC administration on the expression of BCRP in T8
tumors was also assessed by RT-PCR. Administration of a single
FTC IV dose did not appear to cause any major toxicities. The resulting pharmacokinetic data were fit to a two-compartment model using NONMEM and the
FTC clearance was determined to be 0.55 ml/min (25.0 ml/min/kg) with a 56% inter-animal variability. Area under the plasma concentration time curve was determined by Bailer's method and was calculated to be 1128+/-111 microg min/ml.
FTC was widely distributed in all tissues assayed with highest concentrations found in lungs, liver and kidney in decreasing order, respectively.
FTC did not appear to have any effect on the expression of BCRP in T8
tumors. Less than 2% of the administered dose was recovered in the urine and feces after 24 h, suggesting hepatic metabolism as a primary mechanism of elimination. The current study can be used as a basis for future animal or in vivo studies with
FTC designed to further understand the impact of BCRP on drug resistance.