Amodiaquine Metabolism is Impaired by Common Polymorphisms in CYP2C8: Implications for Malaria Treatment in Africa

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 09/2007; 82(2):197-203. DOI: 10.1038/sj.clpt.6100122
Source: PubMed


Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

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Available from: Jean-Bosco Ouédraogo, Apr 26, 2014
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    • "Although serious adverse events are rare in the treatment for uncomplicated malaria, mild events are common. In the particular case of AQ-based treatments, these have been consistently reported (Parikh et al. 2007; Ndiaye et al. 2011). From the present knowledge, the most likely genetic candidates modulating the risk for these events are the polymorphisms at CYP1A1 and CYP1B1, particularly when associated with CYP2C8 variability. "
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    ABSTRACT: Amodiaquine (AQ) is a 4-aminoquinoline widely used in the treatment of malaria as part of the artemisinin combination therapy (ACT). AQ is metabolised towards its main metabolite desethylamodiaquine mainly by cytochrome P450 2C8 (CYP2C8). CYP1A1 and CYP1B1 play a minor role in the metabolism but they seem to be significantly involved in the formation of the short-lived quinine-imine. To complete the genetic variation picture of the main genes involved in AQ metabolism in the Zanzibar population, previously characterised for CYP2C8, we analysed in this study CYP1A1 and CYP1B1 main genetic polymorphisms. The results obtained show a low frequency of the CYP1A1*2B/C allele (2.4%) and a high frequency of CYP1B1*6 (approximately 42%) followed by CYP1B1*2 (approximately 27%) in Zanzibar islands. Genotype data for CYP1A1 and CYP1B1 show a low incidence of fast metabolisers, revealing a relatively safe genetic background in Zanzibar’s population regarding the appearance of adverse effects. L’amodiaquine (AQ) est une 4-aminoquinoléine largement utilisée dans le traitement du paludisme dans le cadre de la thérapie de combinaison à base d’artémisinine (TCA). AQ est métabolisée vers son métabolite majeur, la desethylamodiaquine principalement par le cytochrome P450 2C8 (CYP2C8). Les protéines CYP1A1 et CYP1B1 jouent un rôle mineur dans le métabolisme, mais elles semblent être fortement impliquées dans la formation de quinine-imine transitoire. Afin de compléter le tableau de variation génétique des principaux gènes impliqués dans le métabolisme de l’AQ dans la population de Zanzibar, précédemment caractérisé pour CYP2C8, nous avons analysé dans cette étude les principaux polymorphismes génétiques de CYP1A1 et CYP1B1. Les résultats obtenus montrent une faible fréquence de l’allèle CYP1A1*2B/C (2,4%) et une fréquence élevée de CYP1B1*6 (∼ 42%) suivie par CYP1B1*2 (∼ 27%) dans les îles de Zanzibar. Les données sur le génotype de CYP1A1 et CYP1B1 montrent une faible incidence de métaboliseurs rapides, révélant une base génétique relativement sûre dans la population de Zanzibar pour ce qui concerne l’apparition d’effets indésirables. La amodiaquina (AQ) es una 4-aminoquinolina ampliamente utilizada en el tratamiento de la malaria como parte de la terapia de combinación basada en la artemisinina (ACT). La AQ se metaboliza hacia la desetilamodiaquina - su principal metabolito - principalmente a través del citocromo P450 2C8 (CYP2C8). CYP1A1 y CYP1B1 juegan un papel menor en el metabolismo, pero parecen estar significativamente implicados en la formación de quinina-iminas de corta vida. En este estudio hemos analizado los principales polimorfismos genéticos de CYP1A1 y CYP1B1 para completar el panorama de variación genética de los principales genes involucrados en el metabolismo de la AQ en la población de Zanzíbar, previamente caracterizada para CYP2C8. Los resultados obtenidos muestran una baja frecuencia, en las islas Zanzíbar, del alelo CYP1A1*2B/C (2.4%) y una alta frecuencia de CYP1B1*6 (∼42%) seguido por CYP1B1*2 (∼27%). Los datos de genotipaje de CYP1A1 y CYP1B1 muestran una baja incidencia de metabolitos rápidos, revelando un contexto genético relativamente seguro con respecto a la aparición de efectos adversos en la población de Zanzíbar.
    Preview · Article · May 2012 · Tropical Medicine & International Health
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    • "The prevalence of this allele is reported to be 13.9% in Zanzibar [5], whereas in Ghana it ranges between 16.8% and 17.9% [14-16]. Two studies had been conducted in Burkina Faso, the former showed a CYP2C8*2 prevalence of 11.5% in the south of the country [12]. In the second study, sympatric ethnic groups living in the central area of Burkina Faso were analysed: the Fulani showed a prevalence of 9.9% and the Mossi-Rimaibè group 23.7% [3]. "
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    ABSTRACT: The aim of this study was to investigate cytochrome P450 2C8*2 (CYP2C8*2) distribution and allele frequency in three populations from West and East Africa exposed to Plasmodium falciparum malaria. CYP2C8 enzyme is involved in the metabolism of the anti-malarials amodiaquine and chloroquine. The presence of the CYP2C8*2 defective allele has been recently associated to higher rate of chloroquine-resistant malaria parasites. A total of 503 young subjects were genotyped for the single nucleotide polymorphism rs11572103 (A/T). Eighty-eight were from southern Senegal, 262 from eastern Uganda and 153 from southern Madagascar. The PCR-RFLP technique was used to discriminate the wild-type (A) from the defective allele (T). A CYP2C8*2 (T) allele frequency of 0.222 ± 0.044 was detected in Senegal, 0.105 ± 0.019 in Uganda and 0.150 ± 0.029 in Madagascar. This study demonstrated that CYP2C8*2 allele is widespread in Africa. This allele occurs at different frequency in West and East Africa, being higher in Senegal than in Uganda and Madagascar. These data indicate that an important fraction of the populations analysed has a decreased enzymatic activity, thus being at higher risk for drug accumulation with two possible consequences: i) an exacerbation of drug-associated adverse side effects; ii) an increase of drug-resistance selection pressure on P. falciparum parasites.
    Full-text · Article · Apr 2012 · Malaria Journal
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    • "The metabolism is catalyzed by a polymorphic isoform of hepatic cytochrome P450 2C8 (CYP2C8). Four CYP2C8 variant alleles namely CYP2C8*2, CYP2C8*3, CYP2C8*4 and CYP2C8*5 code for enzymes with decreased activity (Dai et alet al., 2001), (Li et alet al., 2002), (Parikh et alet al., 2007), (Soyama et al., 2002). "
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    ABSTRACT: Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively. In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population. In this randomized crossover study, loose and AS/AQ formulations were administered to normal healthy volunteers (n = 24) over two study phases. The drugs' tolerabilities (incidence of facial flushing, giddiness, headache, nausea, abdominal discomfort, progression of liver enzymes and neutrophil counts) were compared between the two treatment arms. Volunteers were also genotyped for the CYP2C8 and CYP2A6 variants. The frequency of the CYP2A6*1B, CYP2A6*4, CYP2A6*8 and CYP2A6*9 alleles were 54.2%, 16.7%, 4.2% and 10.4%, respectively. No mutations for CYP2C8 gene were, however, detected. Most (96%) of the subjects were of the Malay ethnicity. Subjects having the CYP2A6*1B variants responsible for ultra rapid metabolism of AS suffered a significantly higher incidence of ADRs. Our study is the first to report that CYP2A6 genotyping influences AS's ADR. Gender also plays a role where females reported more incidences of nausea (p < 0.05). It is concluded that genetic polymorphisms of CYP2A6 as well as gender influence the side effect profiles of subjects receiving AS among this Malaysian population.
    Full-text · Article · Apr 2012 · Toxicology mechanisms and methods
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