Plasmodium falciparum malaria is one of the most important infectious diseases in the developing world, representing a priority in public health mainly in sub-Saharan Africa. Nowadays, anti-malarial strategies include: the development of a vaccine, the vector control, as well as drug treatment, which remains the most effective remedy to clear the infection. However, the spread of anti-malarial drug-resistance affects the outcome of treatments [
1], since
P. falciparum has selected resistant strains for the majority of the molecules used in anti-malarial therapy [
2]. As recently demonstrated, host genetic variation in drug metabolizing enzymes influences the selection of
P. falciparum drug-resistance in Burkina Faso [
3]. In particular, the cytochrome P450 2 C8 (CYP2C8), a polymorphic enzyme that mainly contributes to the hepatic metabolism of amodiaquine (AQ) and chloroquine (CQ), shows a genetic variant (
CYP2C8*2) that is associated with higher rate of drug-resistant parasites in the infected host (
pfcrt-76Y and
pfmdr1-86Y
P. falciparum alleles) [
3].
CYP2C8 is a member of the human CYP2C enzyme family, which also includes CYP2C9, CYP2C18 and CYP2C19, whose genes are located on the chromosome 10q24 [
4]. Human CYP2C8 is involved in the metabolism of a variety of clinically important drugs, including the anti-malarials AQ, CQ and, to a lesser extent, dapsone (DDS) [
4]. CYP2C8 is the only enzyme involved in the biotransformation of AQ [
4], whereas for CQ it plays a major role [
5,
6], the secondary routes for CQ metabolism being limited by genetic and inhibitory factors in Africans [
3,
5‐
11].
CYP2C8 gene is known to be polymorphic, and the distribution of variant alleles differs among ethnic populations [
4].
CYP2C8*2, the variant most common in Africans, is related to a poor metabolizer phenotype (PM) in subjects carrying at least one copy of the defective allele [
4,
9]. Subjects who are poor metabolizers experience a longer drug half-life [
12] and have increased adverse side effects. In particular,
CYP2C8*2 shows six fold lower intrinsic clearance of AQ than wild type [
12]. On the other hand, no evidence is yet available from the literature about the role of
CYP2C8 genetic variance in CQ pharmacokinetics [
13], although there is indirect evidence of lower CQ metabolism in
CYP2C8*2-carriers shown through the association between the allele and rates of CQ-resistant
P. falciparum parasites [
3]. In humans, CQ concentrations decline multi-exponentially and elimination at its initial anti-malarial concentrations is relatively rapid. This means that it usually persists for only a few days at concentrations sufficient to select resistant over sensitive parasites (its window of selection). The poor metabolizers obviously greatly extent these windows. A slower metabolism of an anti-malarial drug leads to a longer time of parasite exposure to a sub-therapeutic level of the molecule, therefore acting as a further co-factor in drug-resistance selection. Few studies had described the
CYP2C8*2 allele frequency in Africa, and the actual knowledge of its distribution is incomplete all over the continent. The prevalence of this allele is reported to be 13.9% in Zanzibar [
5], whereas in Ghana it ranges between 16.8% and 17.9% [
14‐
16]. Two studies had been conducted in Burkina Faso, the former showed a
CYP2C8*2 prevalence of 11.5% in the south of the country [
12]. In the second study, sympatric ethnic groups living in the central area of Burkina Faso were analysed: the Fulani showed a prevalence of 9.9% and the Mossi-Rimaibè group 23.7% [
3]. Moreover, Dai et al. [
17] reported a value of 18% in African-Americans.
CYP2C8*2 is virtually absent in non-African populations [
17], as in Caucasians, where instead the poor metabolizer allele is represented by
CYP2C8*3, which is absent or found at very low frequency in Africa [
17].
Actually, the official policies for the treatment of uncomplicated forms of
P. falciparum malaria are based on artemisinin combination therapy (ACT), including the association of artesunate with AQ. However, CQ is still used as anti-malarials in several African countries [
18‐
22]. Moreover, the CQ tablets are often of poor quality [
23,
24] and the compliance to the therapy is low and then the selective effects on parasite are improved.