Pharmacokinetic rationale fortheinteraction of 5-fluorouracil andmisonidazole inhumans

SummaryAspartofa PhaseIclinical trial, 5 patients received 5-fluorouracil (FU)bothsingly andin combination withmisonidazole (MISO)forthetreatment ofgastrointestinal cancer.Concentrations oftotal FU andF-containing metabolites inurine specimens, taken during 48hafter therapy, were determined. The clearance ofFU following administration of1.0 or 1.5gFU m-2was significantly reduced bytreatment with MISO(1.75-2.0 gm2) given 2hprior toFU therapy. Reduced clearance ofFU byMISO was associated withan earlier onsetoftheperiod ofnonlinearity ofFU pharmacokinetics andan increased half-life of elimination. Furthermore, theclearance ofFU correlated inversely withtheseverity ofgastrointestinal toxicity. Themechanism ofMISOenhancement ofFU action isunlikely tobecompetition formicrosomal enzymes, as proposed fortheinteraction ofMISO andalkylating agents, since FU iscatabolized at mitochondrial andcytosolic sites. Thereisconsiderable evidence frominvitro andin vivostudies inanimals tosuggest thatthe2nitroimidazole, misonidazole (MISO), a radiosensitizer ofhypoxic cells, enhances tumour response tochemotherapy (reviews byMcNally, 1982;Millar,1982;Siemann,1982a). The potentiation mechanism, however, is unclear (reviewed byBrown,1982)andclinical studies (Spooner etal., 1982; Urtasun etal., 1982) are limited. Administration ofMISOsimultaneously with5fluorouracil (FU)inmicebearing Lewislung carcinoma enhanced thetumourresponse assessed byclonogenic cell survival (Stephens etal., 1981). FU-induced growth delay ofthe16/Cmammary carcinoma andtheKHT sarcoma wasincreased by theaddition ofMISO (Tannock, 1980a). Host toxicity, measured bydeathandlossofbody weight, however, wasalsoincreased, resulting in onlyasmall gain intherapeutic index. Since theenhancement ofeffect byMISOoccurs withcytotoxic drugsofdiverse mechanisms of action, Stephens etal.(1981) suggested thatMISO mayalter drugpharmacokinetics, leading togreater exposure tothedrug. Inanimal studies, MISOhas beenshownto alterthepharmacokinetics of alkylating agents (Tannock, 1980b; Stephens etal., 1981; Clutterbuck etal., 1982; Workmanetal., 1983)andnitrosoureas (Tannock, 1980b; Lee& Workman, 1983), buttheeffect ofthesensitizer on drugelimination inhumanshasnotbeenreported.