Academic Journal
Comparative pharmacokinetics and tissue distribution of primaquine enantiomers in mice
| العنوان: | Comparative pharmacokinetics and tissue distribution of primaquine enantiomers in mice |
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| المؤلفون: | Pius S. Fasinu, Narayan D. Chaurasiya, N. P. Dhammika Nanayakkara, Yan‑Hong Wang, H. M. T. Bandara Herath, Bharathi Avula, James D. McChesney, David Jollow, Larry A. Walker, Babu L. Tekwani |
| المصدر: | Malaria Journal, Vol 21, Iss 1, Pp 1-14 (2022) |
| بيانات النشر: | BMC, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Arctic medicine. Tropical medicine LCC:Infectious and parasitic diseases |
| مصطلحات موضوعية: | Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216 |
| الوصف: | Abstract Background Primaquine (PQ) has been used for the radical cure of relapsing Plasmodium vivax malaria for more than 60 years. PQ is also recommended for prophylaxis and prevention of transmission of Plasmodium falciparum. However, clinical utility of PQ has been limited due to toxicity in individuals with genetic deficiencies in glucose 6-phosphate dehydrogenase (G6PD). PQ is currently approved for clinical use as a racemic mixture. Recent studies in animals as well as humans have established differential pharmacological and toxicological properties of the two enantiomers of PQ. This has been attributed to differential metabolism and pharmacokinetics of individual PQ enantiomers. The aim of the current study is to evaluate the comparative pharmacokinetics (PK), tissue distribution and metabolic profiles of the individual enantiomers in mice. Methods Two groups of 21 male Albino ND4 Swiss mice were dosed orally with 45 mg/kg of S-(+)-PQ and R-(−)PQ respectively. Each of the enantiomers was comprised of a 50:50 mixture of 12C- and 13C- stable isotope labelled species (at 6 carbons on the benzene ring of the quinoline core). Three mice were euthanized from each group at different time points (at 0, 0.5, 1, 2, 4, 8, 24 h) and blood was collected by terminal cardiac bleed. Liver, spleen, lungs, kidneys and brain were removed, extracted and analysed using UPLC/MS. The metabolites were profiled by tandem mass (MS/MS) fragmentation profile and fragments with 12C–13C twin peaks. Non-compartmental analysis was performed using the Phoenix WinNonLin PK software module. Results The plasma AUC0-last (µg h/mL) (1.6 vs. 0.6), T1/2 (h) (1.9 vs. 0.45), and Tmax (h) (1 vs. 0.5) were greater for SPQ as compared to RPQ. Generally, the concentration of SPQ was higher in all tissues. At Tmax, (0.5–1 h in all tissues), the level of SPQ was 3 times that of RPQ in the liver. Measured Cmax of SPQ and RPQ in the liver were about 100 and 40 times the Cmax values in plasma, respectively. Similar observations were recorded in other tissues where the concentration of SPQ was higher compared to RPQ (2× in the spleen, 6× in the kidneys, and 49× in the lungs) than in the plasma. CPQ, the major metabolite, was preferentially generated from RPQ, with higher levels in all tissues (> 10× in the liver, and 3.5× in the plasma) than from SPQ. The PQ-o-quinone was preferentially formed from the SPQ (> 4× compared to RPQ), with higher concentrations in the liver. Conclusion These studies show that in mice, PQ enantiomers are differentially biodistributed and metabolized, which may contribute to differential pharmacologic and toxicity profiles of PQ enantiomers. The findings on higher levels of PQ-o-quinone in liver and RBCs compared to plasma and preferential generation of this metabolite from SPQ are consistent with the higher anti-malarial efficacy of SPQ observed in the mouse causal prophylaxis test, and higher haemolytic toxicity in the humanized mouse model of G6PD deficiency. Potential relevance of these findings to clinical use of racemic PQ and other 8-aminoquinolines vis-à-vis need for further clinical evaluation of individual enantiomers are discussed. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1475-2875 |
| Relation: | https://doaj.org/toc/1475-2875 |
| DOI: | 10.1186/s12936-022-04054-4 |
| URL الوصول: | https://doaj.org/article/0b7d431ad13d471f97a9489095c3c336 |
| رقم الانضمام: | edsdoj.0b7d431ad13d471f97a9489095c3c336 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14752875 |
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| DOI: | 10.1186/s12936-022-04054-4 |