TY - JOUR T1 - Regional Pharmacokinetics of Amifostine in Anesthetized Dogs: Role of the Liver, Gastrointestinal Tract, Lungs, and Kidneys JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1425 LP - 1430 DO - 10.1124/dmd.30.12.1425 VL - 30 IS - 12 AU - Micha Levi AU - James A. Knol AU - William D. Ensminger AU - Susan J. DeRemer AU - Chunzhi Dou AU - Susan M. Lunte AU - Heather S. Bonner AU - Leslie M. Shaw AU - David E. Smith Y1 - 2002/12/01 UR - http://dmd.aspetjournals.org/content/30/12/1425.abstract N2 - 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. In this study, we characterized the sites and extent of organ-specific activation by the liver, gastrointestinal tract, lungs, and kidneys after systemic administrations of amifostine. A total of 10 dogs were infused via the cephalic vein using sequential dose rates of drug at 0.125, 0.500, and 1.00 μmol/min/kg. Infusion of each dose rate lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, pulmonary artery, and renal vein). The hepatic arterial, portal venous, and renal arterial blood flows, and cardiac output, were measured. The hepatic and splanchnic extraction of amifostine remained high at 90%, whereas gastrointestinal extraction decreased from 43 to 12 to 15% with increasing dose. Pulmonary extraction of amifostine was low at 7%, whereas renal extraction was intermediate at 57%. Because blood flow measurements were relatively constant during the drug infusions, clearance parameters paralleled that of organ extraction. As a result, saturability was observed in the gastrointestinal blood clearance (i.e., from 9.8 to 2.8–3.3 ml/min/kg) and total body plasma clearance of amifostine (i.e., from 52.6 to about 37.3 ml/min/kg), as the doses increased. Due to the drug's high activation in liver, these findings suggest that amifostine may offer good protection of this organ against the toxicities of chemotherapy and radiation. The American Society for Pharmacology and Experimental Therapeutics ER -