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

Abstract

Aims: To investigate the impact of Plasmodium vivax malaria and chloroquineprimaquine 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 (AUC 0-12h). 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. The authors confirm that the Principal Investigator for this paper is Wuelton Marcelo Monteiro and that he had direct clinical responsibility for patients.

Clinical treatment for hepatitis C reverses CYP2C19 inhibition

“…The data also show that CYP2C19 metabolic activity does not differ between patients with mild to moderate hepatic fibrosis (fibrosis stages F0/F1 and F2) and patients with advanced liver fibrosis (F3 and F4) after treatment with DAAs for HCV. In addition to HCV infection, other studies from our research group have also demonstrated that CYP2C19 inhibition was at least partially reversed after treatment for other infectious diseases with a key inflammatory component, such as visceral leishmaniasis and malaria 9,10 . Through the lens of translational pharmacology, the present study reinforces that the administration of drugs which are substrates for CYP2C19 (amitriptyline, clomipramine, clopidogrel, hexobarbital, imipramine, lansoprazole, melatonin, nelfinavir, omeprazole, pantoprazole, progesterone, proguanil, R‐mephobarbital, ranitidine, S‐mephenytoin, venlafaxine, voriconazole) 42 before or during the treatment with DAAs for HCV should take into account the dosing regimen, once the activity of this CYP isoform is inhibited, similar to what has been shown in the past for parasitic infections.…”

“…In vitro , 7 in silico 6,8 and clinical 9,10 studies demonstrate that high plasma concentrations of IL‐6 suppress the expression and, consequently, the activity of multiple CYP isoforms. Plasma concentrations of interleukin 6 (IL‐6) in healthy volunteers range from 1 to 10 pg mL −1 , but may increase to 10‐1500 pg mL −1 in patients with inflammatory diseases, such as rheumatoid arthritis 6,8 .…”

Monitoring Plasmodium vivax resistance to antimalarials: Persisting challenges and future directions

“…On the other hand, CQ can partially inhibit CYP2D6 activity, as evaluated by the phenotypic probes debrisoquine ( Adedoyin et al, 1998 ) and metoprolol ( Lancaster et al, 1990 ; Almeida et al, 2020 ), thereby decreasing the generation of pharmacologically active PQ metabolites. A decrease in CYP2D6-mediated biotransformation might explain the increased plasma levels of PQ and cPQ measured in healthy individuals co-administered CQ and PQ, compared with those given PQ alone ( Pukrittayakamee et al, 2014 ).…”

Impact of CYP2D6 Genetic Variation on Radical Cure of Plasmodium vivax Malaria

“…(see above). However, it should be emphasized that in both studies, the cohort of decreased CYP2D6 activity (AS ≤ 1) included none 23 or few (< 6%) 14 poor metabolizers (AS = 0) and consequently the apparent lack of association between decreased CYP2D6 activity and anti‐relapse efficacy of tafenoquine may not be extrapolated to poor metabolizers. This is especially relevant in view of the evidence from murine malaria models that the anti‐relapse effect of tafenoquine is abolished by CYP2D knock‐out, which may be seen as equivalent to the human CYP2D6 poor metabolizer phenotype (AS = 0), rather than intermediate metabolizer phenotypes.…”

“…We have recently verified the inhibitory effect of chloroquine on CYP2D6‐mediated hydroxylation in patients with P . vivax and discussed this finding in the context of apparent discrepancy between the well‐demonstrated enhancement of primaquine anti‐malarial efficacy by chloroquine and the notion that CYP2D6 activity is essential to the anti‐malarial efficacy of primaquine 23 …”