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Review
. 2007 Feb;8(2):187-98.
doi: 10.2217/14622416.8.2.187.

CYP2C8 and antimalaria drug efficacy

J P Gil  1 , E Gil Berglund
Affiliations
Review

CYP2C8 and antimalaria drug efficacy

J P Gil et al. Pharmacogenomics. 2007 Feb.

Abstract

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.

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Figures

Figure 1.
Figure 1.. CYP2C8 gene and known single nucleotide polymorphisms .
Only the single nucleotide polymorphisms present in the coding region of the gene are represented. ºAlleles coding for documented or predicted reduced enzyme activity; *2: Two-fold higher KM for paclitaxel transformation ; *3: 15% of *1-associated turnover number ; *5: Expected to be an inactive gene ; *7: No in vitro detectable activity ; *8: In vitro enzyme activity 10% of the wild-type ; P404A: Reduced protein expression leading to decreased Vmax/KM .
Figure 2.
Figure 2.. Artemisinine combination therapy.
Artemisinine combination therapy is the main hope for the global control of malaria. The strategy is based on an elegant and simple concept, herein depicted from the example of the artesunate–mefloquine combination in current use in Thailand. The very fast parasite reduction rate (PRR) of artesunate (1/10,000)  rapidly reduces the parasite biomass, allowing the partner drug (mefloquine [MQ], with a substantial slower PRR, 1/100) to face a number of parasites several orders of magnitude smaller. No parasites remain when MQ serum concentrations reached subtherapeutic levels where selection of tolerants might ocour. The expected different mechanisms of action of these structurally different drugs, associated with their documented in vitro pharmacodynamic synergy, further contributes to protect the combination from resistance. Figure adapted from and . P. falciparum image courtesy of B Schmidt, Department of Medicine, Karolinska Institute, Sweden.
Figure 3.
Figure 3.. Amodiaquine and its main metabolite desethylamodiaquine.
CYP: Cytochrome P450.
See this image and copyright information in PMC

References

Bibliography

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    2. Excellent review on the concept of artemisinine combined therapy.

    1. Li XQ, Bjorkman A, Andersson TB, Ridderstrom M, Masimirembwa CM: Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J. Pharmacol. Exp. Ther. 300(2) 399–407 (2002). - PubMed

    2. Initial and very complete study pointing to cytochrome P450 (CYP)2C8 as the main enzyme in the metabolism of amodiaquine (AQ).

Websites
    1. Human Cytochrome P450 Allele Nomenclature Committee. www.cypalleles.ki.se/
    1. WHO: Global Malaria Program – treatment policies. www.who.int/malaria/treatmentpolicies.html

    2. Up-to-date database of the national malaria treatment policies.

    1. Medicines for Malaria Venture. www.mmv.org
    1. US Institute of Health artesunate and amodiaquine fixed-dose combination in the treatment of uncomplicated Plasmodium falciparum malaria study. www.clinicaltrials.gov/ct/show/NCT00316 329 - PubMed

MeSH terms