Metabolism of Piperaquine to Its Antiplasmodial Metabolites and Their Pharmacokinetic Profiles in Healthy Volunteers

Abstract

As a partner antimalarial for artemisinin drug-based combination therapy (ACT), piperaquine (PQ) can be metabolized into two major metabolites, including piperaquine -oxide (M1) and piperaquine,-dioxide (M2). To better understand the antimalarial potency of PQ, the antimalarial activity of the PQ metabolites (M1 and M2) was studied (in strains 3D7 andDd2) and (in the murine species) in this study. The recrudescence and survival time of infected mice were also recorded after drug treatment. The pharmacokinetic profiles of PQ and its two metabolites (M1 and M2) were investigated in healthy subjects after oral doses of two widely used ACT regimens, i.e., dihydroartemisinin plus piperaquine phosphate (Duo-Cotecxin) and artemisinin plus piperaquine (Artequick). Remarkable antiplasmodial activity was found for PQ (50% growth-inhibitory concentration [IC], 4.5 nM against 3D7 and 6.9 nM againstDd2; 90% effective dose [ED], 1.3 mg/kg of body weight), M1 (IC, 25.5 nM against 3D7 and 38.7 nM againstDd2; ED, 1.3 mg/kg), and M2 (IC, 31.2 nM against 3D7 and 33.8 nM againstDd2; ED, 2.9 mg/kg). Compared with PQ, M1 showed comparable efficacy in terms of recrudescence and survival time and M2 had relatively weaker antimalarial potency. PQ and its two metabolites displayed a long elimination half-life (∼11 days for PQ, ∼9 days for M1, and ∼4 days for M2), and they accumulated after repeated administrations. The contribution of the two PQ metabolites to the efficacy of piperaquine as a partner drug of ACT for the treatment of malaria should be considered for PQ dose optimization.

Altered Drug Transport by Plasmodium falciparum Chloroquine Resistance Transporter Isoforms Harboring Mutations Associated with Piperaquine Resistance

“…In any case, weak base trapping dictates that weak polyprotic bases like CQ and PPQ will accumulate approximately 1000-fold in the acidic environment of the parasitic DV relative to the cytosol. , Given plasma concentrations for CQ (1–10 μM) , and PPQ (100–1500 nM), , the drug concentrations used in this study to assay PfCRT-mediated drug transport correspond to concentrations of drug found within the parasite DV. These DV concentrations (which are not near the IC 50 concentrations typically measured in parasite growth inhibition assays) are the concentrations of drug to which the DV-disposed face of PfCRT that is believed to initially bind the drug is exposed .…”

“…In this study, we have tested whether several novel PfCRT isoforms recently detected in putatively PPQR P. falciparum Cambodian or South American isolates ,,,,, contribute to PPQR via mediating an increased rate of PPQ transport, similar to how other PfCRT isoform drug transport phenomena have been found to be linked to PfCRT protein-mediated drug resistances. Using a galactose inducible expression system, and noting that human plasma levels of PPQ are much higher than those used in previous in vitro analysis of PPQ transport, we quantified PPQ transport for S. cerevisiae yeast expressing PPQR-associated PfCRT isoforms using physiologically relevant PPQ concentrations. We also tested whether PPQR-associated PfCRT mutations alter CQ transport relative to previously studied CQR-associated PfCRT isoforms from which the PPQR-associated isoforms are derived.…”

Promising nanomaterials in the fight against malaria

“…This approach is, however, a matter of debate, because the time during which one of the drugs is present might be long enough to stimulate resistance evolution. 31 Although CQ has an excellent absorption and circulation time profile, 32 its widespread use in the past triggered the emergence of resistance. 33 As a result, CQ is not widely used as first line treatment anymore, being only recommended in areas where resistances are not described in non-falciparum malaria.…”

In Vivo Efficacy and Metabolism of the Antimalarial Cycleanine and Improved In Vitro Antiplasmodial Activity of Semisynthetic Analogues

“…Study on the metabolism of drugs can help to further understand their pharmacokinetics, efficacy, and safety ( 27 ). For example, metabolites of piperaquine were shown to have stronger antiplasmodial activity ( 28 ). However, there have been only a few in vivo metabolism studies of BBIQ alkaloids.…”