Metabolism of primaquine in normal human volunteers: investigation of phase I and phase II metabolites from plasma and urine using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry.
| Title: | Metabolism of primaquine in normal human volunteers: investigation of phase I and phase II metabolites from plasma and urine using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. |
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| Authors: | Avula B; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Tekwani BL; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA. btekwani@olemiss.edu.; Chaurasiya ND; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Fasinu P; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Dhammika Nanayakkara NP; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Bhandara Herath HMT; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Wang YH; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Bae JY; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Khan SI; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Elsohly MA; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; McChesney JD; Ironstone Separations, Inc., 147 CR 245, Etta, MS, 38627, USA.; Zimmerman PA; Center for Global Health & Diseases, Case Western Reserve University Cleveland, Ohio, 44106, USA.; Khan IA; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.; Walker LA; National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA. |
| Source: | Malaria journal [Malar J] 2018 Aug 13; Vol. 17 (1), pp. 294. Date of Electronic Publication: 2018 Aug 13. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 101139802 Publication Model: Electronic Cited Medium: Internet ISSN: 1475-2875 (Electronic) Linking ISSN: 14752875 NLM ISO Abbreviation: Malar J Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : BioMed Central, [2002- |
| MeSH Terms: | Antimalarials/*metabolism ; Primaquine/*metabolism; Antimalarials/blood ; Antimalarials/urine ; Primaquine/blood ; Primaquine/urine ; Adult ; Chromatography, High Pressure Liquid ; Female ; Humans ; Male ; Mass Spectrometry ; Middle Aged |
| Abstract: | Background: 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. 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.; Methods: These 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.; Results: Besides 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.; Conclusion: 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 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. |
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| Grant Information: | R01 AI097366 United States AI NIAID NIH HHS; W81XWH-13-2-0026 Medical Research and Materiel Command; W81XWH-15-1-0704 Medical Research and Materiel Command; OPP53288 Bill and Melinda Gates Foundation |
| Contributed Indexing: | Keywords: 8-aminoquinoline; Antimalarial; Cytochrome P450; Drug metabolism; Malaria; Plasmodium vivax; Primaquine; UHPLC-QToF-MS |
| Substance Nomenclature: | 0 (Antimalarials); MVR3634GX1 (Primaquine) |
| Entry Date(s): | Date Created: 20180815 Date Completed: 20190102 Latest Revision: 20240329 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC6090659 |
| DOI: | 10.1186/s12936-018-2433-z |
| PMID: | 30103751 |
| Database: | MEDLINE |
Journal Article