Pharmacokinetic rationale for the interaction of 5-fluorouracil and misonidazole in humans.
As part of a Phase I clinical trial, 5 patients received 5-fluorouracil (FU) both singly and in combination with misonidazole (MISO) for the treatment of gastrointestinal cancer. Concentrations of total FU and F-containing metabolites in urine specimens, taken during 48 h after therapy, were determined. The clearance of FU following administration of 1.0 or 1.5 g FU m2 was significantly reduced by treatment with MISO (1.75-2.0 gm-2) given 2 h prior to FU therapy. Reduced clearance of FU by MISO was associated with an earlier onset of the period of nonlinearity of FU pharmacokinetics and an increased half-life of elimination. Furthermore, the clearance of FU correlated inversely with the severity of gastrointestinal toxicity. The mechanism of MISO enhancement of FU action is unlikely to be competition for microsomal enzymes, as proposed for the interaction of MISO and alkylating agents, since FU is catabolized at mitochondrial and cytosolic sites.
D000328:Adult; D000368:Aged; D004341:Drug Evaluation; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use* / Q000652:urine; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000652:urine; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000627:therapeutic use*; D009325:Nausea / Q000139:chemically induced; D009593:Nitroimidazoles / Q000627:therapeutic use*; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced
D009593:Nitroimidazoles; D008920:Misonidazole; D005472:Fluorouracil