CYP2C8 and antimalaria drug efficacy.
Malaria is a major infectious disease. In the last 10 years it has killed more than 20 million people, mainly small children in Africa. The highly efficacious artemisinine combination therapy is being launched globally, constituting the main hope for fighting the disease. Amodiaquine is a main partner in these combinations. Amodiaquine is almost entirely metabolized by the polymorphic cytochrome P450 (CYP) isoform 2C8 to the pharmacologically active desethylamodiaquine. The question remains whether the efficacy of amodiaquine is affected by the gene polymorphism. Genotype-inferred low metabolizers are found in 1-4% of African populations, which corresponds to millions of expected exposures to the drug. In vivo pharmacokinetic data on amodiaquine is limited. By combining it with published in vitro pharmacodynamic and drug metabolism information, we review and predict the possible relevance, or lack of, of CYP2C8 polymorphisms in the present and future efficacy of amodiaquine. Chloroquine and dapsone, both substrates of CYP2C8, are also discussed in the same context.
Gil
J P
JP
Karolinska Institute, Malaria Research Unit, Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital, M9:02, KS 17176 Stockholm, Sweden. jose.pedro.gil@ki.se
Gil Berglund
E
E
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics; D013379:Substrate Specificity / Q000187:drug effects
D000962:Antimalarials; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8