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Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2007 Aug; Vol. 82 (2), pp. 197-203. Date of Electronic Publication: 2007 Mar 14. - Publication Year :
- 2007
-
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.
- Subjects :
- Alkynes
Amodiaquine analogs & derivatives
Amodiaquine pharmacology
Antimalarials metabolism
Antimalarials pharmacology
Aryl Hydrocarbon Hydroxylases genetics
Benzoxazines metabolism
Benzoxazines pharmacology
Burkina Faso
Chromatography, High Pressure Liquid
Cyclopropanes
Cytochrome P-450 CYP2C8
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors metabolism
Enzyme Inhibitors pharmacology
Genotype
HIV Protease Inhibitors metabolism
HIV Protease Inhibitors pharmacology
Humans
Lopinavir
Malaria, Falciparum genetics
Malaria, Falciparum metabolism
Models, Biological
Pyridines metabolism
Pyridines pharmacology
Pyrimidinones metabolism
Pyrimidinones pharmacology
Pyrones metabolism
Pyrones pharmacology
Reverse Transcriptase Inhibitors metabolism
Reverse Transcriptase Inhibitors pharmacology
Saquinavir metabolism
Saquinavir pharmacology
Spectrophotometry, Ultraviolet
Sulfonamides
Treatment Outcome
Trimethoprim metabolism
Trimethoprim pharmacology
Amodiaquine metabolism
Aryl Hydrocarbon Hydroxylases metabolism
Malaria, Falciparum drug therapy
Polymorphism, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0009-9236
- Volume :
- 82
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 17361129
- Full Text :
- https://doi.org/10.1038/sj.clpt.6100122