Document Detail


Polymorphism of antimalaria drug metabolizing, nuclear receptor, and drug transport genes among malaria patients in Zanzibar, East Africa.
MedLine Citation:
PMID:  18223457     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Artemisinin-based combination therapy is a main strategy for malaria control in Africa. Zanzibar introduced this new treatment policy in 2003. The authors have studied the prevalence of a number of functional single nucleotide polymorphisms (SNPs) in genes associated with the elimination of the artemisinin-based combination therapy compounds in use in Zanzibar to investigate the frequencies of subgroups potentially at higher drug exposure and therefore possible higher risk of toxicity. One hundred three unrelated children with uncomplicated malaria from the Unguja and Pemba islands of Zanzibar were enrolled. With use of polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR-based allele discrimination methods, the CYP2B6 (G15631T), CYP3A4 (A-392G), CYP3A5 (A6986G, G14690A, 27131-132 insT, C3699T) SNPs and MDR1 SNPs C3435T, G2677T/A, and T-129C were analyzed. PCR product sequencing was applied to regulatory regions of MDR1, the CYP3A4 proximal promoter, and to exons 2 and 5 of PXR, a gene coding for a nuclear factor activated by artemisinin antimalarials and associated with the transcription induction of most of the studied genes. Homozygous subjects for alleles coding for low activity proteins were found at the following frequencies: 1) MDR1: 2.9%; 2) CYP2B6: 9.7%; 3) CYP3A5: 14.1%; and 4) CYP3A4: 49.5%. No functionally relevant allele was found in the analyzed regions of PXR. A new MDR1 SNP was found (T-158C), located in a putative antigen recognition element. Ten (10.1%) subjects were predicted to be low metabolizers simultaneously for CYP3A4 and CYP3A5. This fraction of the population is suggested to be under higher exposure to certain antimalarials, including lumefantrine and quinine.
Authors:
Pedro Eduardo Ferreira; Maria Isabel Veiga; Isa Cavaco; J Paulo Martins; Björn Andersson; Shaliya Mushin; Abullah S Ali; Achuyt Bhattarai; Vera Ribeiro; Anders Björkman; José Pedro Gil
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Therapeutic drug monitoring     Volume:  30     ISSN:  0163-4356     ISO Abbreviation:  Ther Drug Monit     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-01-28     Completed Date:  2008-05-08     Revised Date:  2009-11-03    
Medline Journal Info:
Nlm Unique ID:  7909660     Medline TA:  Ther Drug Monit     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10-5     Citation Subset:  IM    
Affiliation:
Malaria Research Laboratory, Unit of Infectious Diseases, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Antimalarials / pharmacokinetics*
Artemisinins / pharmacokinetics
Child, Preschool
Cytochrome P-450 Enzyme System / genetics*
Female
Humans
Malaria / drug therapy,  metabolism*
Male
P-Glycoprotein / genetics*
Polymerase Chain Reaction
Polymorphism, Single Nucleotide*
Receptors, Steroid / genetics*
Tanzania
Chemical
Reg. No./Substance:
0/ABCB1 protein, human; 0/Antimalarials; 0/Artemisinins; 0/P-Glycoprotein; 0/Receptors, Steroid; 0/pregnane X receptor; 63968-64-9/artemisinine; 9035-51-2/Cytochrome P-450 Enzyme System

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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