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. 2021 Apr;87(4):1859-1868.
doi: 10.1111/bcp.14574. Epub 2020 Oct 25.

Impact of Plasmodium vivax malaria and antimalarial treatment on cytochrome P450 activity in Brazilian patients

Anne Cristine Almeida  1   2 , Anna Beatriz Ribeiro Elias  3 , Maria Paula Marques  4 , Gisely Cardoso de Melo  1   2 , Allyson Guimarães da Costa  2   5 , Erick Frota Gomes Figueiredo  1   2 , Larissa Wanderley Brasil  1   2 , Fernanda Rodrigues-Soares  6 , Wuelton Marcelo Monteiro  1   2 , Marcus Vinicius Guimarães de Lacerda  1   7 , Vera Lucia Lanchote  4 , Guilherme Suarez-Kurtz  3
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Free article

Impact of Plasmodium vivax malaria and antimalarial treatment on cytochrome P450 activity in Brazilian patients

Anne Cristine Almeida et al. Br J Clin Pharmacol. 2021 Apr.
Free article

Abstract

Aims: To investigate the impact of Plasmodium vivax malaria and chloroquine-primaquine chemotherapy on CYP2D6 and CYP2C19 activity in patients from the Brazilian Amazon.

Methods: Adult patients (n = 30) were given subtherapeutic doses of CYP2D6 and CYP2C19 phenotypic probes metoprolol (10 mg) and omeprazole (2 mg) in three different stages of vivax malaria illness: acute disease (study phase 1), post chemotherapy (phase 2) and convalescence (stage 3). Plasma concentrations of probes and CYP-hydroxylated metabolites (α-OH metoprolol and 5-OH omeprazole) were measured using LC/MS/MS. Two pharmacokinetic metrics were used to estimate CYP activity: (a) ratio of plasma concentrations of probe/metabolite at 240 minutes after administration of the probes and (b) ratio of areas under the time-concentration curves for probe/metabolite (AUC0-12h ). For statistical analysis, the pharmacokinetic metrics were normalized to the respective values in phase 3. Taqman assays were used for CYP2D6 and CYP2C19 genotyping. Cytokines levels were measured using cytometric bead array.

Results: Both pharmacokinetic metrics for metoprolol and omeprazole, and plasma concentrations of cytokines IL-6, IL-8 and IL-10 varied significantly across the three study phases (ANOVA P < 0.0001). Post hoc tests showed greater metoprolol:α-OH metoprolol ratios in phases 1 and 2 compared to phase 3, larger omeprazole:5-OH omeprazole ratios in phase 1 than in phases 2 and 3, and higher circulating IL-6, IL-8 and IL-10 in phase 1 than in phases 2 and 3.

Conclusion: P. vivax malaria and treatment altered CYP2D6 and CYP2C19 metabolic phenotypes. CYP2C19 inhibition is attributed to a higher level of circulating proinflammatory cytokines, while suppression of CYP2D6 is ascribed mainly to chloroquine exposure.

Keywords: Brazilian Amazon; CYP2C19; CYP2D6; Plasmodium vivax malaria; chloroquine; cytokines; primaquine.

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References

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