Vol. 30, Issue 12, 1425-1430, December 2002

Regional Pharmacokinetics of Amifostine in Anesthetized Dogs: Role of the Liver, Gastrointestinal Tract, Lungs, and Kidneys

Micha Levi, James A. Knol, William D. Ensminger, Susan J. DeRemer, Chunzhi Dou, Susan M. Lunte, Heather S. Bonner, Leslie M. Shaw, and David E. Smith

College of Pharmacy (M.L., D.E.S.), Upjohn Center for Clinical Pharmacology (M.L., S.J.D., C.D., W.D.E., D.E.S.), Departments of Pharmacology and Internal Medicine (W.D.E.) and Surgery (J.A.K.), University of Michigan, Ann Arbor, Michigan; Department of Pharmaceutical Chemistry (S.M.L.), University of Kansas, Lawrence, Kansas; and Department of Pathology (H.S.B., L.M.S.), Laboratory of Medicine, Philadelphia, Pennsylvania

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.