TO THE EDITOR—We have read with great interest the article by Paganotti et al [1], in which evidence is presented about the possible influence of human pharmacogenetics on the development of chloroquine (CQ) resistance by Plasmodium falciparum. This prompted us to hypothesize that such influence would be more visible and significant when considering the structurally related amodiaquine (AQ). In fact, although CYP2C8 is a secondary player in the metabolism of CQ [2], it is essential for the cytochrome P450 (CYP) associated biotransformation of AQ to its therapeutically main active metabolite, desethylamodiaquine (DEAQ)[3]. The in vivo parasite response to AQ therapy is modulated by polymorphisms in the P. falciparum multidrug resistance 1 gene (pfmdr1), particularly those concerning the N86Y [4], Y184F, and D1246Y [5, 6] single-nucleotide polymorphisms (SNPs). Accordingly, we hypothesized that the CYP2C8 status of the target population would influence the intensity of posttreatment selection of these polymorphisms. Such events should be reflected in significant differences in the frequencies of these SNPs between parasites recurrently infecting patients carrying wild-type CYP2C8* 1/* 1 and those infecting subjects harboring minor CYP2C8 alleles coding for activitycompromised enzymes. In this context, the Zanzibari population offers the advantage of being an African native population with very high prevalence of the CYP2C8* 3 allele, which codes for a verylow-activity enzyme [7].

We retrospectively analyzed the CYP2C8 status of patients experiencing recurrent parasitemia in 2 similar trials on the efficacy of ASAQ for uncomplicated P. falciparum malaria [5, 8]. Both trials had a 42-day follow-up period and were performed at a time when malaria transmission was still high in Zanzibar.