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Influence of amifostine on the pharmacokinetics of cisplatin in cancer patients

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Author: Korst, A.E.C. · Sterre, M.L.T. van der · Gall, H.E. · Fichtinger-Schepman, A.M.J. · Vermorken, J.B. · Vijgh, W.J.F. van der
Type:article
Date:1998
Institution: Centraal Instituut voor Voedingsonderzoek TNO
Source:Clinical Cancer Research, 2, 4, 331-336
Identifier: 234360
Keywords: Nutrition · Amifostine · Cisplatin · Creatinine · Adult · Aged · Area under the curve · Clinical article · Creatinine blood level · Dna adduct · Dna drug complex · Drug blood level · Drug effect · Drug half life · Female · Human · Intravenous drug administration · Kidney function · Male · Malignant neoplastic disease · Priority journal · Amifostine · Antineoplastic Agents · Cisplatin · DNA Adducts · Drug Interactions · Female · Half-Life · Hemofiltration · Humans · Leukocytes · Male · Middle Aged · Neoplasms · Platinum · Radiation-Protective Agents

Abstract

The pharmacokinetics of cisplatin was investigated in 13 patients receiving 18 courses of cisplatin alone or in combination with amifostine to investigate the influence of amifostine (WR 2721; Ethyol) on the pharmacokinetics of cisplatin. Cisplatin was administered as a 1-h i.v. infusion, whereas amifostine was given i.v. over 15 min just before the cisplatin infusion. An increase in the final half-life of ultrafilterable platinum was observed after treatment with cisplatin and amifostine (t( 1/4 ), 0.77 ± 0.10 h; n = 8), compared to cisplatin alone (t( 1/4 ), 0.57 ± 0.15 h; n = 8). This might be caused by an influence of amifostine on the kidney function, because an increase in the serum creatinine levels was also observed 24 h after treatment with cisplatin and amifostine (13.8 ± 12.6%; n = 9), which was not observed after treatment with cisplatin alone (-0.1 ± 6.8%; n = 9). Surprisingly, the final half-life of unchanged cisplatin did not increase, but even showed a slight decrease after treatment with amifostine. In vitro data would suggest that this might be due to a chemical interaction between cisplatin and amifostine. Because the AUC values of ultrafilterable platinum and unchanged cisplatin did not change significantly and no change in Pt-DNA adduct (Pt-GG) levels in leukocytes was observed upon addition of amifostine in the treatment schedule, the change in the pharmacokinetics of cisplatin is most probably of minor importance and has no significant impact on the efficacy of cisplatin, as already confirmed by clinical studies.