Amifostine (Ethyol): pharmacokinetic and pharmacodynamic effects in vivo.

Amifostine (Ethyol) administered to cancer patients is rapidly cleared from plasma by a biphasic decay with an alpha half-life (T1/2 alpha) of 0.88 min and a T1/2 beta of 8.8 min. The result is that more than 90% of the drug has disappeared from the plasma compartment 6 min after intravenous (i.v.) administration. Only approximately 1% of the dose appears in the ascites. Animal studies indicate that amifostine is primarily excreted in urine-approximately 6% of the dose is excreted in the urine as amifostine and its metabolites WR-1065 and disulphides-which means that a large percentage of the dose is taken up by the tissues. Maximal tissue concentrations of WR-1065 and the disulphides were obtained between 10 and 30 min after an intraperitoneal injection of amifostine in mice, with the lowest concentrations in tumour tissues. Because WR-1065 gives protection to normal tissues rather than rescue, the pharmacokinetic data indicate that amifostine must be given shortly before administration of the cytostatic drug or radiation from which protection is required. For these reasons, amifostine is given to patients as a 15-min i.v. infusion before cisplatin and carboplatin to protect against their dose-limiting toxicities. In some regimens carboplatin is combined with three doses of amifostine because of the high concentration of the active carboplatin species during the first 4 h after administration. When carboplatin was administered as a 15-min i.v. infusion of 400 mg/m2 and amifostine as a 15-min i.v. infusion of 740 mg/m2 just before and 2 and 4 h after carboplatin, the area under the plasma concentration-time curve for ultrafilterable platinum increased from 253 +/- 45 microM.h (n = 6) for carboplatin alone to 305 +/- 63 microM.h (n = 11) for carboplatin+three doses of amifostine. Experiments in nude mice bearing OVCAR-3 xenografts showed that amifostine, given once before cisplatin or three times in combination with carboplatin, did not affect the antitumour effect of these drugs. When amifostine was only given just before carboplatin, it even stimulated the antitumour effect of carboplatin significantly.