CYP2C8 polymorphism frequencies among malaria patients in Zanzibar

Cavaco, Isabel; Strömberg-Nörklit, J.; Kaneko, Akira; Msellem, Mwinyi; Dahoma, Mohammed; Ribeiro, Vera; Björkman, Anders; Gil, José Pedro

doi:10.1007/s00228-004-0871-8

Cited by 74 publications

(68 citation statements)

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“…Their frequencies differ significantly both between and within continental populations (Table 5 ancestry. In sub-Saharan African populations, its allele frequency ranges from about 0.10 in a Fulani population in Burkina Faso to 0.37 in a Mbuti pygmy population in Congo (Cavaco et al, 2005;Rower et al, 2005;Parikh et al, 2007;Kudzi et al, 2009;Speed et al, 2009;Paganotti et al, 2011Paganotti et al, , 20121000Genomes Project Consortium, 2012Arnaldo et al, 2013;Marwa et al, 2014). In an African-American population in the New York area, the allele frequency of CYP2C8*2 was 0.10 (Martis et al, 2013).…”

Section: A Population Geneticsmentioning

confidence: 99%

“…In the mixed Brazilian and Ecuadorian populations, its frequency is 0.08 and 0.07, and in a Chilean mestizo population it is 0.06 (Roco et al, 2012;Suarez-Kurtz et al, 2012;Vicente et al, 2014). There is wide variability in the frequency of CYP2C8*3 in sub-Saharan African populations, even within a country (Cavaco et al, 2005;Rower et al, 2005;Parikh et al, 2007;Kudzi et al, 2009;Arnaldo et al, 2013;Staehli Hodel et al, 2013;Marwa et al, 2014;Paganotti et al, 2014). For example, the frequency of CYP2C8*3 was found to be 0.00 in individuals in central Tanzania and as high as 0.10 in the Mwanza region of Tanzania (Staehli Hodel et al, 2013;Marwa et al, 2014).…”

Section: A Population Geneticsmentioning

confidence: 99%

“…In East Asian populations, the frequency of CYP2C8*4 is generally 0.01 or less, but a frequency of 0.02 was seen in an Uighur Chinese population (Nakajima et al, 2003;Muthiah et al, 2005;Speed et al, 2009;1000Genomes Project Consortium, 2012Staehli Hodel et al, 2013;Wu et al, 2013). The allele is rare in individuals with a sub-Saharan African ancestry, with a frequency of below 0.01 in all investigated sub-Saharan African populations and 0.01 in an African American population (Cavaco et al, 2005;Rower et al, 2005;Kudzi et al, 2009;1000Genomes Project Consortium, 2012Arnaldo et al, 2013;Martis et al, 2013).…”

Section: A Population Geneticsmentioning

confidence: 99%

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Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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Section: A Population Geneticsmentioning

confidence: 99%

Section: A Population Geneticsmentioning

confidence: 99%

Section: A Population Geneticsmentioning

confidence: 99%

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Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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“…The gene for CYP2C8 is located in a cluster with the genes for CYP2C9, CYP2C19, and CYP2C18 on chromosome 10q24 (11). CYP2C8*2 and CYP2C8*3 are the two most frequently occurring variant alleles of CYP2C8, and both variants code for enzymes with decreased activity (9,10,23), raising the possibility that polymorphisms in the CYP2C8 gene may modulate the metabolism of AQ (5).…”

mentioning

confidence: 99%

Effect of Concomitant Artesunate Administration and Cytochrome P4502C8 Polymorphisms on the Pharmacokinetics of Amodiaquine in Ghanaian Children with Uncomplicated Malaria

Adjei

Kristensen

Goka

et al. 2008

Antimicrob Agents Chemother

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Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene. A two-compartment model was fitted to 169 plasma DEAQ concentrations from 103 Ghanaian children aged 1 to 14 years with uncomplicated malaria treated either with AQ alone (n ‫؍‬ 15) or with AS plus AQ (n ‫؍‬ 88). The population clearance of DEAQ appeared to increase nonlinearly with body weight, and the central volume of distribution of DEAQ was higher (P < 0.001) in the AS-plus-AQ group than in the AQ-only group. The maximum plasma DEAQ concentration was higher (P < 0.001), and the population distribution half-life was shorter (P < 0.01), in the AQ-only group than in the AS-plus-AQ group. The total areas under the plasma DEAQ concentrationtime curves (P ‫؍‬ 0.68) and elimination half-lives (P ‫؍‬ 0.39) were similar for the two groups. There was a high frequency (0.179) of the non-wild-type allele of CYP2C8, but no differences between CYP2C8 genotypes with regard to AQ efficacy or safety were evident. The sample size, however, was limited, so monitoring of AQ toxicity in the study area is still indicated. The nonlinear clearance of DEAQ and the wide variability in kinetic parameters have safety implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination.Prompt treatment with safe and efficacious antimalarial drugs is an important malaria control strategy. This strategy is being challenged by the escalating resistance of Plasmodium falciparum to the available drugs (33). Artemisinin combination therapy (ACT) is recommended as a rational approach to curb this problem of escalating antimalarial drug resistance (31). Many countries in sub-Saharan Africa have adopted ACT as their first-line malaria treatment policy. The combination of artesunate (AS) with amodiaquine (AQ) is one of the most widely adopted ACT regimens.AQ is a 4-aminoquinoline that is rapidly absorbed and extensively metabolized upon oral administration to desethylamodiaquine (DEAQ), its main and active metabolite (7,8). The formation of DEAQ from AQ is catalyzed by cytochrome P4502C8 (CYP2C8), a polymorphic isoform of hepatic cytochrome P450 (18). The gene for CYP2C8 is located in a cluster with the genes for CYP2C9, CYP2C19, and CYP2C18 on chromosome 10q24 (11). CYP2C8*2 and CYP2C8*3 are the two most frequently occurring variant alleles of CYP2C8, and both variants code for enzymes with decreased activity (9, 10, 23), raising the possibility that polymorphisms in the CYP2C8 gene may modulate the metabolism of AQ (5).AS is ...

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“…In Cambodia, however, its efficacy since 2002 has been reported in all but one study to be considerably and consistently lower (19,20,21). While the influence of nongenetic factors, such as food intake, age, or body weight, on the pharmacokinetics of antimalarial drugs has received some attention, only more recently have the effects of polymorphisms in genes encoding enzymes responsible for antimalarial drug metabolism (such as CYP, NAT2, and UDPglucuronosyltransferase [UGT] gene), received attention (22)(23)(24)(25)(26)(27)(28). Better knowledge of the ethnic variability of genes encoding metabolizing enzymes, and of the impact of this variability on the pharmacokinetic profiles of antimalarial drugs, could help tailor treatments for specific populations.…”

mentioning

confidence: 99%

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Hodel

Csajka

Ariey

et al. 2013

Antimicrob Agents Chemother

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The pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes (CYP, namely, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) and the N-acetyltransferase 2 gene (NAT2) on the pharmacokinetics of artemisininbased combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10 (100C¡T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17 (1023C¡T and 2850C¡T), CYP3A4*1B, NAT2*5, and NAT2*14. For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisininbased combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials.

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CYP2C8 polymorphism frequencies among malaria patients in Zanzibar

Cited by 74 publications

References 20 publications

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Effect of Concomitant Artesunate Administration and Cytochrome P4502C8 Polymorphisms on the Pharmacokinetics of Amodiaquine in Ghanaian Children with Uncomplicated Malaria

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

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