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Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration
Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885159/ https://www.ncbi.nlm.nih.gov/pubmed/36726785 http://dx.doi.org/10.3389/fphar.2022.1104735 |
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author | Khan, Washim Wang, Yan-Hong Chaurasiya, Narayan D. Nanayakkara, N. P. Dhammika Bandara Herath, H. M. Harrison, Kerri A. Dale, Gray Stanford, Donald A. Dahl, Eric P. McChesney, James D. Gul, Waseem ElSohly, Mahmoud A. Jollow, David Tekwani, Babu L. Walker, Larry A. |
author_facet | Khan, Washim Wang, Yan-Hong Chaurasiya, Narayan D. Nanayakkara, N. P. Dhammika Bandara Herath, H. M. Harrison, Kerri A. Dale, Gray Stanford, Donald A. Dahl, Eric P. McChesney, James D. Gul, Waseem ElSohly, Mahmoud A. Jollow, David Tekwani, Babu L. Walker, Larry A. |
author_sort | Khan, Washim |
collection | PubMed |
description | Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days’ treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7–14 days washout period in between: R-(−) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects. |
format | Online Article Text |
id | pubmed-9885159 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98851592023-01-31 Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration Khan, Washim Wang, Yan-Hong Chaurasiya, Narayan D. Nanayakkara, N. P. Dhammika Bandara Herath, H. M. Harrison, Kerri A. Dale, Gray Stanford, Donald A. Dahl, Eric P. McChesney, James D. Gul, Waseem ElSohly, Mahmoud A. Jollow, David Tekwani, Babu L. Walker, Larry A. Front Pharmacol Pharmacology Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days’ treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7–14 days washout period in between: R-(−) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects. Frontiers Media S.A. 2023-01-16 /pmc/articles/PMC9885159/ /pubmed/36726785 http://dx.doi.org/10.3389/fphar.2022.1104735 Text en Copyright © 2023 Khan, Wang, Chaurasiya, Nanayakkara, Bandara Herath, Harrison, Dale, Stanford, Dahl, McChesney, Gul, ElSohly, Jollow, Tekwani and Walker. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Khan, Washim Wang, Yan-Hong Chaurasiya, Narayan D. Nanayakkara, N. P. Dhammika Bandara Herath, H. M. Harrison, Kerri A. Dale, Gray Stanford, Donald A. Dahl, Eric P. McChesney, James D. Gul, Waseem ElSohly, Mahmoud A. Jollow, David Tekwani, Babu L. Walker, Larry A. Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration |
title | Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration |
title_full | Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration |
title_fullStr | Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration |
title_full_unstemmed | Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration |
title_short | Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration |
title_sort | comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885159/ https://www.ncbi.nlm.nih.gov/pubmed/36726785 http://dx.doi.org/10.3389/fphar.2022.1104735 |
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