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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Alkynes
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Amodiaquine / analogs & derivatives
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Amodiaquine / metabolism*
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Amodiaquine / pharmacology
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Antimalarials / metabolism
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Antimalarials / pharmacology
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Aryl Hydrocarbon Hydroxylases / genetics
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Aryl Hydrocarbon Hydroxylases / metabolism*
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Benzoxazines / metabolism
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Benzoxazines / pharmacology
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Burkina Faso
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Chromatography, High Pressure Liquid
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Cyclopropanes
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Cytochrome P-450 CYP2C8
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Dose-Response Relationship, Drug
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Drug Interactions
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Genotype
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HIV Protease Inhibitors / metabolism
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HIV Protease Inhibitors / pharmacology
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Humans
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Lopinavir
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Malaria, Falciparum / drug therapy*
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Malaria, Falciparum / genetics
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Malaria, Falciparum / metabolism
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Models, Biological
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Polymorphism, Genetic*
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Pyridines / metabolism
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Pyridines / pharmacology
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Pyrimidinones / metabolism
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Pyrimidinones / pharmacology
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Pyrones / metabolism
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Pyrones / pharmacology
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Reverse Transcriptase Inhibitors / metabolism
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Reverse Transcriptase Inhibitors / pharmacology
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Saquinavir / metabolism
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Saquinavir / pharmacology
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Spectrophotometry, Ultraviolet
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Sulfonamides
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Treatment Outcome
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Trimethoprim / metabolism
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Trimethoprim / pharmacology
Substances
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Alkynes
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Antimalarials
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Benzoxazines
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Cyclopropanes
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Enzyme Inhibitors
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HIV Protease Inhibitors
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Pyridines
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Pyrimidinones
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Pyrones
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Reverse Transcriptase Inhibitors
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Sulfonamides
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Amodiaquine
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Lopinavir
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desethylamodiaquine
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Trimethoprim
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Aryl Hydrocarbon Hydroxylases
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CYP2C8 protein, human
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Cytochrome P-450 CYP2C8
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efavirenz
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Saquinavir
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tipranavir