Amodiaquine Metabolism is Impaired by Common Polymorphisms in CYP2C8: Implications for Malaria Treatment in Africa

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.

Priority pharmacogenetics for the African continent: focus on CYP450

“…Furthermore, in eastern Africa, where malaria is ranked second in terms of its contribution to DALYs, only two countries have been investigated. In western Africa, where malaria is the highest contributor to disease burden, three countries have allelic frequency data for CYP2C8, namely Burkina Faso [34,35], Ghana [36][37][38] and…”

Induction of Amodiaquine Metabolism by Rifampicin Following Concurrent Administration in Healthy Volunteers

“…33 This is especially true because genetic polymorphisms can characterize CYP2C8 in the metabolism of drugs and provide basis for pharmacokinetic variations in individuals as well as responses to drug actions. 34 There was occurrence of a pronounced increase in the metabolic ratio. This parameter, AUC (metabolite)/AUC (drug), the ratio of AUC of the metabolite to that of the unchanged drug, is a known measure of the extent of metabolism of a drug.…”

Can pharmacogenomics improve malaria drug policy?

“…Two more common CYP2C8 variants, CYP2C8*2 and *3, decrease the metabolizing ability of CYP2C8 as evidenced by reduced clearance of the anticancer drug paclitaxel and arachidonic acid, respectively. 29,30 In fact, CYP2C8*3 displays no detectable metabolizing ability in vitro. 30 In a study by Parikh et al, 275 subjects with malaria from Burkina Faso were evaluated for amodiaquine metabolism.…”

“…29,30 In fact, CYP2C8*3 displays no detectable metabolizing ability in vitro. 30 In a study by Parikh et al, 275 subjects with malaria from Burkina Faso were evaluated for amodiaquine metabolism. 30 The subjects with the CYP2C8*2 genotype (more common African variant) experienced more abdominal pain than subjects with the wild-type (i.e.…”

“…30 In a study by Parikh et al, 275 subjects with malaria from Burkina Faso were evaluated for amodiaquine metabolism. 30 The subjects with the CYP2C8*2 genotype (more common African variant) experienced more abdominal pain than subjects with the wild-type (i.e. the normal, non-mutated gene) (52% versus 30%; P < 0.01).…”