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
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 an...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-08-01
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| Series: | Malaria Journal |
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| Online Access: | http://link.springer.com/article/10.1186/s12936-018-2433-z |
| _version_ | 1811242835219841024 |
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| author | Bharathi Avula Babu L. Tekwani Narayan D. Chaurasiya Pius Fasinu N. P. Dhammika Nanayakkara H. M. T. Bhandara Herath Yan-Hong Wang Ji-Yeong Bae Shabana I. Khan Mahmoud A. Elsohly James D. McChesney Peter A. Zimmerman Ikhlas A. Khan Larry A. Walker |
| author_facet | Bharathi Avula Babu L. Tekwani Narayan D. Chaurasiya Pius Fasinu N. P. Dhammika Nanayakkara H. M. T. Bhandara Herath Yan-Hong Wang Ji-Yeong Bae Shabana I. Khan Mahmoud A. Elsohly James D. McChesney Peter A. Zimmerman Ikhlas A. Khan Larry A. Walker |
| author_sort | Bharathi Avula |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T13:57:01Z |
| format | Article |
| id | doaj.art-654e746afd904edc9c8c9089d7d34a5d |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-04-12T13:57:01Z |
| publishDate | 2018-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-654e746afd904edc9c8c9089d7d34a5d2022-12-22T03:30:20ZengBMCMalaria Journal1475-28752018-08-0117111410.1186/s12936-018-2433-zMetabolism 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 spectrometryBharathi Avula0Babu L. Tekwani1Narayan D. Chaurasiya2Pius Fasinu3N. P. Dhammika Nanayakkara4H. M. T. Bhandara Herath5Yan-Hong Wang6Ji-Yeong Bae7Shabana I. Khan8Mahmoud A. Elsohly9James D. McChesney10Peter A. Zimmerman11Ikhlas A. Khan12Larry A. Walker13National Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiIronstone Separations, Inc.Center for Global Health & Diseases, Case Western Reserve University ClevelandNational Center for Natural Products Research, School of Pharmacy, The University of MississippiNational Center for Natural Products Research, School of Pharmacy, The University of MississippiAbstract 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.http://link.springer.com/article/10.1186/s12936-018-2433-zPrimaquineAntimalarialMalariaPlasmodium vivax8-aminoquinolineDrug metabolism |
| spellingShingle | Bharathi Avula Babu L. Tekwani Narayan D. Chaurasiya Pius Fasinu N. P. Dhammika Nanayakkara H. M. T. Bhandara Herath Yan-Hong Wang Ji-Yeong Bae Shabana I. Khan Mahmoud A. Elsohly James D. McChesney Peter A. Zimmerman Ikhlas A. Khan Larry A. Walker 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 Malaria Journal Primaquine Antimalarial Malaria Plasmodium vivax 8-aminoquinoline Drug metabolism |
| 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 |
| title_full | 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_fullStr | 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_full_unstemmed | 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_short | 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_sort | 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 |
| topic | Primaquine Antimalarial Malaria Plasmodium vivax 8-aminoquinoline Drug metabolism |
| url | http://link.springer.com/article/10.1186/s12936-018-2433-z |
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