Abstract

As a partner antimalarial with an extremely long elimination half-life (~30 days), piperaquine (PQ) is mainly metabolized into a pharmacologically active N-oxide metabolite (PN1) in humans. In the present work, the metabolic retroversion of PQ and PN1, potentially associated with decreased clearance of PQ, was studied. The results showed that interconversion existed for PQ and its metabolite PN1. The N-oxidation of PQ to PN1 was mainly mediated by CYP3A4, and PN1 can rapidly reduce back to PQ via CYP/FMO enzymes. In accordance with these findings, the CYP non-selective inhibitor (1-ABT) or CYP3A4 inhibitor (ketoconazole) inhibited the N-oxidation pathway in liver microsomes (>90%), and the reduction metabolism was inhibited by 1-ABT (>90%) or methimazole (~50%). Based on in vitro physiological and enzyme kinetic studies, quantitative prediction of hepatic clearance (CL_H) of PQ was performed, which indicated its negligible decreased elimination in humans in the presence of futile cycling, with the unbound CL_H decreasing by 2.5% (0.069 l/h/kg); however, a minor decrease in unbound CL_H (by 12.8%) was found in mice (0.024 l/h/kg). After an oral dose of PQ (or PN1) to mice, the parent form predominated in the blood circulation, and PN1 (or PQ) was detected as a major metabolite. Other factors probably associated with delayed elimination of PQ (intestinal metabolism and enterohepatic circulation) did not play a key role in PQ elimination. These data suggested that the metabolic interconversion of PQ and its N-oxide metabolite contributes to but may not significantly prolong its duration in humans.

Significance Statement This paper investigated the interconversion metabolism of PQ and its N-oxide metabolite in vitro as well as in mice. The metabolic profiles of PQ were re-established by this futile cycling, which contributes to but may not significantly prolong its elimination in humans. Enzyme phenotyping indicated a low possibility of interaction of PQ during ACT treatment.