CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine
Abstract Background The 8-aminoquinoline (8AQ) drug primaquine (PQ) is currently the only approved drug effective against the persistent liver stage of the hypnozoite forming strains Plasmodium vivax and Plasmodium ovale as well as Stage V gametocytes of Plasmodium falciparum . To date, several grou...
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ftdoajarticles:oai:doaj.org/article:1c94ac45b6e04f0888bb7f4518a68733 2023-05-15T15:10:40+02:00 CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine Pybus Brandon S Sousa Jason C Jin Xiannu Ferguson James A Christian Robert E Barnhart Rebecca Vuong Chau Sciotti Richard J Reichard Gregory A Kozar Michael P Walker Larry A Ohrt Colin Melendez Victor 2012-08-01T00:00:00Z https://doi.org/10.1186/1475-2875-11-259 https://doaj.org/article/1c94ac45b6e04f0888bb7f4518a68733 EN eng BMC http://www.malariajournal.com/content/11/1/259 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-11-259 1475-2875 https://doaj.org/article/1c94ac45b6e04f0888bb7f4518a68733 Malaria Journal, Vol 11, Iss 1, p 259 (2012) Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2012 ftdoajarticles https://doi.org/10.1186/1475-2875-11-259 2022-12-30T22:47:40Z Abstract Background The 8-aminoquinoline (8AQ) drug primaquine (PQ) is currently the only approved drug effective against the persistent liver stage of the hypnozoite forming strains Plasmodium vivax and Plasmodium ovale as well as Stage V gametocytes of Plasmodium falciparum . To date, several groups have investigated the toxicity observed in the 8AQ class, however, exact mechanisms and/or metabolic species responsible for PQ’s haemotoxic and anti-malarial properties are not fully understood. Methods In the present study, the metabolism of PQ was evaluated using in vitro recombinant metabolic enzymes from the cytochrome P450 (CYP) and mono-amine oxidase (MAO) families. Based on this information, metabolite identification experiments were performed using nominal and accurate mass measurements. Results Relative activity factor (RAF)-weighted intrinsic clearance values show the relative role of each enzyme to be MAO-A, 2C19, 3A4, and 2D6, with 76.1, 17.0, 5.2, and 1.7% contributions to PQ metabolism, respectively. CYP 2D6 was shown to produce at least six different oxidative metabolites along with demethylations, while MAO-A products derived from the PQ aldehyde, a pre-cursor to carboxy PQ. CYPs 2C19 and 3A4 produced only trace levels of hydroxylated species. Conclusions As a result of this work, CYP 2D6 and MAO-A have been implicated as the key enzymes associated with PQ metabolism, and metabolites previously identified as potentially playing a role in efficacy and haemolytic toxicity have been attributed to production via CYP 2D6 mediated pathways. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 11 1 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Pybus Brandon S Sousa Jason C Jin Xiannu Ferguson James A Christian Robert E Barnhart Rebecca Vuong Chau Sciotti Richard J Reichard Gregory A Kozar Michael P Walker Larry A Ohrt Colin Melendez Victor CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background The 8-aminoquinoline (8AQ) drug primaquine (PQ) is currently the only approved drug effective against the persistent liver stage of the hypnozoite forming strains Plasmodium vivax and Plasmodium ovale as well as Stage V gametocytes of Plasmodium falciparum . To date, several groups have investigated the toxicity observed in the 8AQ class, however, exact mechanisms and/or metabolic species responsible for PQ’s haemotoxic and anti-malarial properties are not fully understood. Methods In the present study, the metabolism of PQ was evaluated using in vitro recombinant metabolic enzymes from the cytochrome P450 (CYP) and mono-amine oxidase (MAO) families. Based on this information, metabolite identification experiments were performed using nominal and accurate mass measurements. Results Relative activity factor (RAF)-weighted intrinsic clearance values show the relative role of each enzyme to be MAO-A, 2C19, 3A4, and 2D6, with 76.1, 17.0, 5.2, and 1.7% contributions to PQ metabolism, respectively. CYP 2D6 was shown to produce at least six different oxidative metabolites along with demethylations, while MAO-A products derived from the PQ aldehyde, a pre-cursor to carboxy PQ. CYPs 2C19 and 3A4 produced only trace levels of hydroxylated species. Conclusions As a result of this work, CYP 2D6 and MAO-A have been implicated as the key enzymes associated with PQ metabolism, and metabolites previously identified as potentially playing a role in efficacy and haemolytic toxicity have been attributed to production via CYP 2D6 mediated pathways. |
format |
Article in Journal/Newspaper |
author |
Pybus Brandon S Sousa Jason C Jin Xiannu Ferguson James A Christian Robert E Barnhart Rebecca Vuong Chau Sciotti Richard J Reichard Gregory A Kozar Michael P Walker Larry A Ohrt Colin Melendez Victor |
author_facet |
Pybus Brandon S Sousa Jason C Jin Xiannu Ferguson James A Christian Robert E Barnhart Rebecca Vuong Chau Sciotti Richard J Reichard Gregory A Kozar Michael P Walker Larry A Ohrt Colin Melendez Victor |
author_sort |
Pybus Brandon S |
title |
CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine |
title_short |
CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine |
title_full |
CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine |
title_fullStr |
CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine |
title_full_unstemmed |
CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine |
title_sort |
cyp450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine |
publisher |
BMC |
publishDate |
2012 |
url |
https://doi.org/10.1186/1475-2875-11-259 https://doaj.org/article/1c94ac45b6e04f0888bb7f4518a68733 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 11, Iss 1, p 259 (2012) |
op_relation |
http://www.malariajournal.com/content/11/1/259 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-11-259 1475-2875 https://doaj.org/article/1c94ac45b6e04f0888bb7f4518a68733 |
op_doi |
https://doi.org/10.1186/1475-2875-11-259 |
container_title |
Malaria Journal |
container_volume |
11 |
container_issue |
1 |
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1766341649822121984 |