Effects of Genetic Variation at the CYP2C19 / CYP2C9 Locus on Pharmacokinetics of Chlorcycloguanil in Adult Gambians

Abstract

Aims-Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria. Materials & methods-Polymorphisms in CYP2C19and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated.Results-All CYP2C19/CYP2C9 alleles obeyed Hardy-Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus time curve at 24 h (AUC 0-24 ) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C max (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071).Conclusion-CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus. Financial & competing interests disclosureWe thank the Medical Research Council (MRC) and the European and Developing Countries Clinical Trials Partnership (EDCTP) for funding this study through a PhD fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Ethical conduct of researchThe authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. Antimalarial biguanides are converted to their active metabolite by cytochrome P450 enzymes and these metabolites inhibit the malaria parasite's dihydrofolate reductase enzyme. Other metabolites such as 4-chlorophenylbiguanide and dichlorophenylbiguanide are also produced; however, they are not thought to have antimalarial activity [5][6][7]. In the atovaquone-proguanil combination, synergism arises from enhancement of the membrane collapsing activity of atovaquone by proguanil, however, in other combinations and when used alone the effect on folate metabolism is thought to be most important [8]. Europe PMC Funders GroupThe biguanides have the advantage of relatively short duration of action and thus may be less likely to select resistant parasites than other antimalarial compounds [9]. Biguanide combinations that have been evaluated for malaria therapy include chlorproguanil-dapsone (Lapdap™) and chlorproguanil-dapsone-artesunate (CDA, Dacart™), which have completed Phase III studies. However, due to concerns about increased risk of anemia, particularly in patients who are glucose-6-pho...

CYP2C19*17 increases clopidogrel‐mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel

“…Although there was a tendency for higher concentrations of cycloguanil and 4‐chlorphenylbiguanide, our data do not support the hypothesis that proguanil metabolism is increased in CYP2C19*17 carriers and, hence, that the enzyme activity is higher in these subjects. This is not in agreement with a previous study that found increased metabolism of the structurally similar drug chlorproguanil in Gambian malaria patients carrying the CYP2C19*17 allele . It should be noted that atovaquone, which is both a substrate and an inhibitor of CYP3A4, has been suggested to counteract the impact of CYP2C19*17 .…”

“…This is not in agreement with a previous study that found increased metabolism of the structurally similar drug chlorproguanil in Gambian malaria patients carrying the CYP2C19*17 allele. 51 It should be noted that atovaquone, which is both a substrate and an inhibitor of CYP3A4, has been suggested to counteract the impact of CYP2C19*17. [53][54][55] However, such an interaction has only been shown at steady state, where the repetitive dosing will accumulate atovaquone to a clinically important level.…”

“…Clinical studies have indicated that low CYP2C19 activity influences the disposition, efficacy and toxicity of proguanil, although the correlation between efficacy and cycloguanil concentration is not evident . In a study of Gambian malaria patients treated with the analogous drug chlorproguanil, patients with the CYP2C19*17 allele had increased formation of the CYP2C19‐catalysed metabolite chlorcycloguanil …”

“…50 In a study of Gambian malaria patients treated with the analogous drug chlorproguanil, patients with the CYP2C19*17 allele had increased formation of the CYP2C19-catalysed metabolite chlorcycloguanil. 51 The main purpose of the present prospective in vivo study was to investigate the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel in a panel study. The underlying hypothesis was that the formation of the metabolites and the effect of clopidogrel are increased in carriers of CYP2C19*17.…”

Pharmacogenomics of Antimicrobial Agents

“…A study in Gambian adults with uncomplicated malaria showed that ultrarapid metabolizers ( CYP2C19*17 homozygotes) had higher AUC and C max values for these active metabolites [59]. However, other studies showed no association between CYP2C19 polymorphisms and breakthrough parasitemia, treatment failure, ex vivo antimalarial activity or mild adverse events, possible reflecting compensatory metabolism by CYP3A4 (reviewed in [17]).…”