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BACKGROUND Piperaquine (PQ) and its pharmacologically active metabolite PQ N-oxide (PM1) can be metabolically interconverted via hepatic cytochrome P450 and FMO enzymes. OBJECTIVES The reductive metabolism of PM1 and its further N-oxidation metabolite (PM2) by intestinal microflora was evaluated, and its role in PQ elimination was also investigated. METHOD The hepatic and microbial reduction metabolism of PM1 and PM2 was studied in vitro. The reaction phenotyping experiments were performed using correlation analysis, selective chemical inhibition, and human recombinant CYP/FMO enzymes. The role of microbial reduction metabolism in PQ elimination was evaluated in mice pretreated with antibiotics. The effect of the reduction of metabolism on PQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. RESULTS Both hepatic P450/FMOs enzymes and microbial nitroreductases (NTRs) contributed to the reduction metabolism of two PQ N-oxide metabolites. In vitro physiologic and enzyme kinetic studies of both N-oxides showed a comparable intrinsic clearance by the liver and intestinal microflora. Pretreatment with antibiotics did not lead to a significant (P > 0.05) change in PQ pharmacokinetics in mice after an oral dose. The predicted pharmacokinetic profiles of PQ in humans did not show an effect of metabolic recycling. CONCLUSIONS Microbial NTRs and hepatic P450/FMO enzymes contributed to the reduction metabolism of PQ N-oxide metabolites. The reduction in metabolism by intestinal microflora did not affect PQ clearance, and the medical warning in patients with NTRs-related disease (e.g., hyperlipidemia) will not be clinically meaningful.