Delayed gametocyte clearance in Plasmodium vivax malaria is associated with polymorphisms in the cytochrome P450 reductase (CPR)

• Published in: Antimicrobial agents and chemotherapy Vol. 68; no. 4; p. e0120423
• Main Authors: Salazar, Yanka Evellyn Alves Rodrigues, Louzada, Jaime, Puça, Maria Carolina Silva de Barros, Guimarães, Luiz Felipe Ferreira, Vieira, José Luiz Fernandes, Siqueira, André Machado de, Gil, José Pedro, Brito, Cristiana Ferreira Alves de, Sousa, Tais Nobrega de
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 03.04.2024
• Subjects: Antimalarials - pharmacology; Antimalarials - therapeutic use; Antimicrobial Chemotherapy; Artemisinins - pharmacology; Chloroquine - pharmacology; Cytochrome P-450 CYP2D6 - genetics; Epidemiology and Surveillance; Humans; Malaria - drug therapy; Malaria, Falciparum - drug therapy; Malaria, Vivax - drug therapy; NADPH-Ferrihemoprotein Reductase; Plasmodium falciparum; Plasmodium vivax - genetics; Primaquine - pharmacology; Primaquine - therapeutic use; Plasmodium vivax; primaquine; cytochrome P450 reductase; CYP2D6; gametocytes; malaria; pharmacogenetics
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/aac.01204-23

Primaquine (PQ) is the main drug used to eliminate dormant liver stages and prevent relapses in malaria. It also has an effect on the gametocytes of ; however, it is unclear to what extent PQ affects gametocytes. PQ metabolism involves multiple enzymes, including the highly polymorphic CYP2D6 and the cytochrome P450 reductase (CPR). Since genetic variability can impact drug metabolism, we conducted an evaluation of the effect of CYP2D6 and CPR variants on PQ gametocytocidal activity in 100 subjects with malaria. To determine gametocyte density, we measured the levels of transcripts in samples taken before treatment (D0) and 72 hours after treatment (D3). Generalized estimating equations (GEEs) were used to examine the effects of enzyme variants on gametocyte densities, adjusting for potential confounding factors. Linear regression models were adjusted to explore the predictors of PQ blood levels measured on D3. Individuals with the mutation showed a smaller decrease in gametocyte transcript levels on D3 compared to those without the mutation ( = 0.02, by GEE). Consistent with this, higher PQ blood levels on D3 were associated with a lower reduction in transcripts. Based on our findings, the variant plays a role in the persistence of gametocyte density in malaria. Conceptually, our work points to pharmacogenetics as a non-negligible factor to define potential host reservoirs with the propensity to contribute to transmission in the first days of CQ-PQ treatment, particularly in settings and seasons of high human-biting rates.