Abstract
BackgroundPrimaquine (PQ), an 8-aminoquinoline, is the only drug approved by the United States Food and Drug Administration for radical cure and prevention of relapse in Plasmodium vivax infections. Knowledge of the metabolism of PQ is critical for understanding the therapeutic efficacy and hemolytic toxicity of this drug. Recent in vitro studies with primary human hepatocytes have been useful for developing the ultra high-performance liquid chromatography coupled with high-resolution mass spectrometric (UHPLC-QToF-MS) methods for simultaneous determination of PQ and its metabolites generated through phase I and phase II pathways for drug metabolism.MethodsThese methods were further optimized and applied for phenotyping PQ metabolites from plasma and urine from healthy human volunteers treated with single 45 mg dose of PQ. Identity of the metabolites was predicted by MetaboLynx using LC–MS/MS fragmentation patterns. Selected metabolites were confirmed with appropriate standards.ResultsBesides PQ and carboxy PQ (cPQ), the major plasma metabolite, thirty-four additional metabolites were identified in human plasma and urine. Based on these metabolites, PQ is viewed as metabolized in humans via three pathways. Pathway 1 involves direct glucuronide/glucose/carbamate/acetate conjugation of PQ. Pathway 2 involves hydroxylation (likely cytochrome P450-mediated) at different positions on the quinoline ring, with mono-, di-, or even tri-hydroxylations possible, and subsequent glucuronide conjugation of the hydroxylated metabolites. Pathway 3 involves the monoamine oxidase catalyzed oxidative deamination of PQ resulting in formation of PQ-aldehyde, PQ alcohol and cPQ, which are further metabolized through additional phase I hydroxylations and/or phase II glucuronide conjugations.ConclusionThis approach and these findings augment our understanding and provide comprehensive view of pathways for PQ metabolism in humans. These will advance the clinical studies of PQ metabolism in different populations for different therapeutic regimens and an understanding of the role these play in PQ efficacy and safety outcomes, and their possible relation to metabolizing enzyme polymorphisms.
Highlights
Primaquine (PQ), an 8-aminoquinoline, is the only drug approved by the United States Food and Drug Administration for radical cure and prevention of relapse in Plasmodium vivax infections
Avula et al Malar J (2018) 17:294. This approach and these findings augment our understanding and provide comprehensive view of pathways for PQ metabolism in humans. These will advance the clinical studies of PQ metabolism in different popula‐ tions for different therapeutic regimens and an understanding of the role these play in PQ efficacy and safety out‐ comes, and their possible relation to metabolizing enzyme polymorphisms
Primaquine alcohol, 2-hydroxyprimaquine, 3-hydroxyprimaquine, 4-hydroxyprimaquine, 5-hydroxyprimaquine, primaquine-5,6-ortho-quinone, primaquine N-carbamoyl glucuronide, primaquine methyl carbamate, carboxy primaquine lactam, carboxy primaquine methyl ester and primaquine N-acetate were synthesized at National Center for Natural Products Research (NCNPR) and their identity and purity were confirmed by spectral data (IR, NMR and High-Resolution MS) and comparison of their physical data (m.p.) with published values [20, 21]
Summary
Primaquine (PQ), an 8-aminoquinoline, is the only drug approved by the United States Food and Drug Administration for radical cure and prevention of relapse in Plasmodium vivax infections. Primaquine (PQ), an 8-aminoquinoline, is the only drug approved by the US FDA for treatment and radical cure of relapsing Plasmodium vivax malaria [1]. The oxidation products have been identified as metabolites of PQ in the biological fluids of experimental animals treated with PQ. These putative hydroxylated metabolites have been observed to cause oxidative damage to normal and G6PD-deficient erythrocytes [14,15,16,17]
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