Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa.

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Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL

Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa.

Clin Pharmacol Ther. 2007 Aug;82(2):197-203. doi: 10.1038/sj.clpt.6100122. Epub 2007 Mar 14.

PubMed ID

17361129 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Saquinavir	Cytochrome P450 2C8	Protein	Humans	Unknown	Inhibitor	Details

Drug Interactions

Drugs	Interaction
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