Influence of amifostine on the pharmacokinetics of cisplatin in cancer patients.
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 (t1/2, 0.77 +/- 0.10 h; n = 8), compared to cisplatin alone (t1/2, 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.
Korst
A E
AE
Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
van der Sterre
M L
ML
Gall
H E
HE
Fichtinger-Schepman
A M
AM
Vermorken
J B
JB
van der Vijgh
W J
WJ
D000328:Adult; D000368:Aged; D004999:Amifostine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018736:DNA Adducts / Q000097:blood; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006440:Hemofiltration; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D010984:Platinum / Q000097:blood; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018736:DNA Adducts; D011837:Radiation-Protective Agents; C057270:cisplatin-DNA adduct; D010984:Platinum; D004999:Amifostine; D002945:Cisplatin