Pharmacokinetic rationale for the interaction of 5-fluorouracil and misonidazole in humans.

B J Mcdermott,R F Murphy,H W Van Den Berg,W M Martin

doi:10.1038/bjc.1983.253

Abstract

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.

Highlights

This paper describes a preliminary study of the pharmacokinetics of FU and of FU with concurrent administration of MISO for gastrointestinal cancer as part of a Phase I clinical trial
The elimination of total drug for each patient after the administration of different dosages of FU alone and of FU with MISO is shown in Figure 1 a-e
After administration of 1.0 g FU m-2, enhancement of the extent of saturation of drug elimination by MISO was noticeable in 3 patients (Figure 1 a, d, e) but an opposite effect was observed (Figure ic)

Summary

Introduction

The elimination of total drug for each patient after the administration of different dosages of FU alone and of FU with MISO is shown in Figure 1 a-e. The pharmacokinetic profiles are composed of linear and nonlinear kinetics as demonstrated previously for the elimination of FU in patients receiving therapeutic doses for breast cancer (McDermott et al, 1982).

Results

Conclusion