Pharmacology of 5'-deoxy-5-fluorouridine in patients with resistant ovarian cancer.
The pharmacokinetics of the new fluoropyrimidine 5'-deoxy-5-fluorouridine (5'-dFUrd) was investigated in twelve patients. The kinetics of the main metabolite 5-fluorouracil (5-FUra) was studied in eight patients and those of 5,6-dihydro-5-fluorouracil (5-FUraH2) in five patients. The patients participated in a Phase II study performed to investigate the response rate of 5'-dFUrd in advanced ovarian cancer. The pharmacokinetic data were compared with the clinical effects of the drug. The parent drug and 5-FUra were measured in both plasma and urine by high performance liquid chromatography. 5-FUraH2 concentrations in plasma were determined by capillary gas chromatography using electron capture detection and nitrogen-phosphorus specific detection. Several pharmacokinetic parameters such as elimination half-life, mean residence time, and steady state volumes of distribution are presented for 5'-dFUrd, 5-FUra, and 5-FUraH2. Two patients showed a partial response, four had stable disease, and five had progressive disease; one patient died due to myelotoxicity. The severity of the side effects correlated with the mean residence times of 5'-dFUrd and 5-FUra. Low pretreatment serum creatinine clearance (due to renal impairment) correlated with low renal excretion of 5'-dFUrd and a long mean residence time of 5'-dFUrd with the sum of observed toxicity. However, the extent of degradation of 5-FUra to 5-FUraH2 may also be related to the severity of the toxicity of 5'-dFUrd.
de Bruijn
E A
EA
van Oosterom
A T
AT
Tjaden
U R
UR
Reeuwijk
H J
HJ
Pinedo
H M
HM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism*; D005260:Female; D005467:Floxuridine / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D005467:Floxuridine; C019389:5-fluorodihydrouracil; D005472:Fluorouracil; C025034:doxifluridine