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

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT: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 mol/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 effect of etoricoxib on kidney ischemia–reperfusion injury in rats: A biochemical and immunohistochemical assessment

“…In addition, substances which inhibit cytochrome-C translocation have been reported to suppress the caspase-3 activation and increase the rate of Bcl-2 [44]. However, there are also studies indicating that some of the factors which release the cytochrome-C enzyme from the mitochondria into cytoplasm are in fact caspase-3 [45].…”

Amifostine—Antioxidant Drug in Anticancer Therapy

“…Pharmacokinetic data of amifostine and its metabolites in patients have been previously reported by Korst et al (1997) (Table 3). However, the precise mechanisms are still investigated (Culy and Spencer 2001;Levi et al 2002). Hitherto it has been presented that amifostine is not active after oral administration; therefore, it is frequently injected intravenously in the antineoplastic therapy, and its maximum concentration in the blood is observed just after a few minutes following the administration (Capizzi 1999).…”

Early and long-term pulmonary complications of radiotherapy of Hodgkin's lymphoma

“…Де сятилетия исследовательских работ привели к созда нию и внедрению в клинику препарата амифостин, показавшего свою эффективность в качестве анти оксиданта [43]. Учитывая, что результаты, оценен ные в процессе клинических исследований, сущест венно уступали предварительным, полученным на кроликах, можно предполагать, что конкурентными "потребителями" амифостина являются печень и поч ки, в результате чего накопление амифостина в лег ких оказалось менее ожидаемого [44].…”