Metabolic Retroversion of Piperaquine (PQ) via Hepatic Cytochrome P450–Mediated <i>N</i>-Oxidation and Reduction: Not an Important Contributor to the Prolonged Elimination of PQ

Xie, Yuewu; Zhang, Yunrui; Liu, Huixiang; Xing, Jie

doi:10.1124/dmd.120.000306

Cited by 4 publications

(1 citation statement)

References 41 publications

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“…3), had been extensively used as a monotherapy but it is now commonly used as a partner drug with dihydroartemisinin in the ACT. Piperaquine is metabolized primarily by CYP3A4 and CYP3A5 into two major metabolites, piperaquine N-oxide and piperaquine N, N-dioxide, and both metabolites are biologically active contributing to the e cacy of piperaquine [47]. The variants of CYP3A4 and CYP3A5 genes and their occurrence frequencies are shown in Table 1.…”

Section: Piperaquinementioning

confidence: 99%

Insights and Current Perspectives on Pharmacogenomics of Antimalarial Drugs

Soyinka

Nnadi

Onyeji

2022

Preprint

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Malaria constitutes a major public health concern in tropical and other malaria-endemic regions. Genetic and non-genetic factors are known to influence the pharmacokinetics and/or pharmacodynamics of drugs including antimalarial drugs resulting in variability in drug responses. This article aimed to update perspectives on pharmacogenomics and also provide an updated appraisal of genetic variability in drug-metabolizing enzymes which alter the disposition of antimalarial drugs causing variations in treatment outcomes. Important literature databases such as Elsevier, IEEExplore, Pubmed, Scopus, Web of Science, Google Scholar, ProQuest, ScienceDirect, and BioMed Central were selected based on the quality, extant content, and broad area of the discipline. The specific keywords related to the study were identified and used for the study purposedly to identify related works. Advances in genetic research have facilitated the identification of Single Nucleotide Polymorphisms (SNPs) that alter the activity of drug-metabolizing enzymes that metabolize most antimalarial drugs. There is an association between isoforms of CYP450 gene variants and the efficacy of some antimalarial drugs, and this can be applied to the optimization of malarial therapy. Although identification of cytochrome P450 (CYP450) gene variants can be used for personalization of malaria treatment, several challenges are encountered in this process but some resources provide education and guidelines on how to use the pharmacogenetic results of specific drugs.

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Section: Piperaquinementioning

confidence: 99%

Insights and Current Perspectives on Pharmacogenomics of Antimalarial Drugs

Soyinka

Nnadi

Onyeji

2022

Preprint

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The effect of malaria-induced alteration of metabolism on piperaquine disposition in Plasmodium yoelii infected mice and predicted in malaria patients

Xie,

Zhang,

Lin

et al. 2024

International Journal of Antimicrobial Agents

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No Effect of PXR (8055C>T) Polymorphism on the Pharmacokinetic Profiles of Piperaquine in Healthy Chinese Subjects

Liu

Xie

Cai

et al. 2022

CDM

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Background: Significant inter-subject variability in pharmacokinetics and clinical outcomes has been observed for the antimalarial agent piperaquine (PQ). PQ is metabolized by CYP3A4, mainly regulated by pregnane X receptor (PXR). CYP3A4(*1B) polymorphism did not affect PQ clearance. Objectives: The effect of PXR (8055C>T) polymorphism on the pharmacokinetic profiles of PQ was investigated. Method: The pharmacokinetic profiles of PQ and its major metabolite PQ N-oxide (PQM) were studied in healthy Chinese subjects after recommended oral doses of artemisinin-PQ. Twelve subjects were genotyped using PCR-RFLP (six in each group with PXR 8055CC and 8055TT), and plasma concentrations were determined by a validated LC/MS/MS method. The dose-adjusted exposure (AUC and Cmax) to PQ or PQM was investigated, and the metabolic capability of PQ N-oxidation was determined by AUCPQM/AUCPQ. The antimalarial outcome of PQ was evaluated using its day 7 concentration. Results: PQM formation was mediated by CYP3A4/3A5. Interindividual variability in dose-adjusted AUC of PQ and PQM was relatively low (%CV, <30.0%), whereas a larger inter-variability was observed for Cmax values (%CV, 68.1% for PQ). No polymorphic effect was found for PXR (C8055T) on the pharmacokinetic profiles of PQ or its Cday 7 concentrations. Conclusions: Both CYP3A4 and CYP3A5 were involved in PQ clearance. The genotypes of PXR (C8055T) may not contribute to the variability in PQ pharmacokinetics as well as antimalarial outcomes. There might be a low risk of variable exposures to PQ in malaria patients carrying mutated PXR (8055C>T) genes, which deserves further study especially in a larger sample size.

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Metabolic Retroversion of Piperaquine (PQ) via Hepatic Cytochrome P450–Mediated N-Oxidation and Reduction: Not an Important Contributor to the Prolonged Elimination of PQ

Cited by 4 publications

References 41 publications

Insights and Current Perspectives on Pharmacogenomics of Antimalarial Drugs

Insights and Current Perspectives on Pharmacogenomics of Antimalarial Drugs

The effect of malaria-induced alteration of metabolism on piperaquine disposition in Plasmodium yoelii infected mice and predicted in malaria patients

No Effect of PXR (8055C>T) Polymorphism on the Pharmacokinetic Profiles of Piperaquine in Healthy Chinese Subjects

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