INHIBITION OF SULFAMETHOXAZOLE HYDROXYLAMINE FORMATION BY FLUCONAZOLEIN HUMAN LIVER-MICROSOMES AND HEALTHY-VOLUNTEERS

Sulfamethoxazole toxicity is putatively initiated by the formation of a hydroxylamine metabolite by cytochromes P450, If this reaction could be inhibited, toxicity may decrease, We have studied-in vitro and in vivo-fluconazole, ketoconazole, and cimetidine as potentially suitable clinical inhibitors of sulfa methoxazole hydroxylamine formation. Bot h fluconazole and ketoconazole in human liver microsomal incubations c ompetitively inhibited sulfamethoxazole N-hydroxylation, with the inhi bitory constant (K-i) values of 3.5 and 6 mu mol/L, respectively. Cime tidine exhibited a mixed type of inhibition of sulfamethoxazole hydrox ylamine formation in human liver microsomes with IC50 values (the conc entration required to decrease hydroxylamine formation by 50%) of 80 a nd 800 mu mol/L, the lower value being observed when cimetidine was pr eincubated with microsomes and reduced nicotinamide adenine dinucleoti de phosphate. In an in vivo study in six healthy volunteers the inhibi tion of the cytochrome P450-mediated generation of the toxic metabolit e in the presence of fluconazole was shown by a 94% decrease in the ar ea under the plasma concentration-time curve of sulfamethoxazole hydro xylamine. In contrast, the recovery of hydroxylamine in urine decrease d by only 60%. Total clearance of sulfamethoxazole was decreased 26% b y fluconazole, most likely because of the inhibition of unidentified P 450 elimination pathways. There was close agreement between the predic ted (87%) and observed inhibition (94%) of sulfamethoxazole hydroxylam ine formation in vivo. Similarly, there was close agreement between in vivo and in vitro K-i values-1.6 and 3.5 mu mol/L, respectively.