Open Access Research

The metabolism of primaquine to its active metabolite is dependent on CYP 2D6

Brandon S Pybus1*, Sean R Marcsisin1, Xiannu Jin1, Gregory Deye1, Jason C Sousa1, Qigui Li1, Diana Caridha1, Qiang Zeng1, Gregory A Reichard1, Christian Ockenhouse1, Jason Bennett1, Larry A Walker2, Colin Ohrt1 and Victor Melendez1

Author Affiliations

1 Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA

2 National Center for Natural Products Research and Department of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA

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Malaria Journal 2013, 12:212  doi:10.1186/1475-2875-12-212

Published: 20 June 2013

Abstract

Background

The efficacy of the 8-aminoquinoline (8AQ) drug primaquine (PQ) has been historically linked to CYP-mediated metabolism. Although to date no clear evidence exists in the literature that unambiguously assigns the metabolic pathway or specific metabolites necessary for activity, recent literature suggests a role for CYP 2D6 in the generation of redox active metabolites.

Methods

In the present study, the specific CYP 2D6 inhibitor paroxetine was used to assess its effects on the production of specific phenolic metabolites thought to be involved in PQ efficacy. Further, PQ causal prophylactic (developing liver stage) efficacy against Plasmodium berghei in CYP 2D knockout mice was assessed in comparison with a normal C57 background and with humanized CYP 2D6 mice to determine the direct effects of CYP 2D6 metabolism on PQ activity.

Results

PQ exhibited no activity at 20 or 40 mg/kg in CYP 2D knockout mice, compared to 5/5 cures in normal mice at 20 mg/kg. The activity against developing liver stages was partially restored in humanized CYP 2D6 mice.

Conclusions

These results unambiguously demonstrate that metabolism of PQ by CYP 2D6 is essential for anti-malarial causal prophylaxis efficacy.