Author:
Potter Brittney M. J.,Xie Lisa H.,Vuong Chau,Zhang Jing,Zhang Ping,Duan Dehui,Luong Thu-Lan T.,Bandara Herath H. M. T.,Dhammika Nanayakkara N. P.,Tekwani Babu L.,Walker Larry A.,Nolan Christina K.,Sciotti Richard J.,Zottig Victor E.,Smith Philip L.,Paris Robert M.,Read Lisa T.,Li Qigui,Pybus Brandon S.,Sousa Jason C.,Reichard Gregory A.,Marcsisin Sean R.
Abstract
ABSTRACTPrimaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studiedin vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference28 articles.
1. Korean vivax malaria. V. Cure of the infection by primaquine administered during long-term latency;Am J Trop Med Hyg,1953
2. Primaquine, SN 13272, a new curative agent in vivax malaria; a preliminary report;J Natl Malar Soc,1950
3. Primaquine in vivax malaria: an update and review on management issues;Malar J,2011
4. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study;Lancet,2014
5. Single-dose radical cure of Plasmodium vivax: a step closer;Lancet,2014
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