In this article, we will discuss Amifostine (Clinical Pharmacology). So, let’s get started.
Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of
radiation on normal oral tissues. The ability of Amifostine to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol
metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation.
Clinical pharmacokinetic studies show that Amifostine is rapidly cleared from the
plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of Amifostine remains in the plasma 6 minutes after drug administration. Amifostine is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m² of Amifostine, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found
in bone marrow cells 5-8 minutes after intravenous infusion of Amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on Amifostine pharmacokinetics.