Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo
Details
Serval ID
serval:BIB_B3A8434770B5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo
Journal
Pharmacogenetics and Genomics
ISSN
1744-6872 (Print)
Publication state
Published
Issued date
09/2005
Volume
15
Number
9
Pages
599-608
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Sep
Research Support, Non-U.S. Gov't --- Old month value: Sep
Abstract
OBJECTIVES: The human immunodeficiency virus protease inhibitor nelfinavir is substrate of polyspecific drug transporters encoded by ABCB1 (P-glycoprotein), ABCC1 (MRP1) and ABCC2 (MRP2), and an inhibitor of BCRP, encoded by ABCG2. Genetic polymorphism in these genes may be associated with changes in transport function. METHODS: A comprehensive evaluation of single nucleotide polymorphisms (39 SNPs in ABCB1, 7 in ABCC1, 27 in ABCC2, and 16 in ABCG2), and inferred haplotypes was done to assess possible associations of genetic variants with cellular exposure of nelfinavir in vivo. Analysis used peripheral mononuclear cells from individuals receiving nelfinavir (n=28). Key results were re-examined in a larger sample size (n=129) contributing data on plasma drug levels. RESULTS AND CONCLUSIONS: There was no significant association between cellular nelfinavir area under the curve (AUC) and SNPs or haplotypes at ABCC1, ABCC2, ABCG2. There was an association with cellular exposure for two loci in strong linkage disequilibrium: ABCB1 3435C>T; AUCTT>AUCCT>AUCCC (ratio 2.1, 1.4, 1, Ptrend=0.01), and intron 26 +80T>C; AUCCC> AUCCT > AUCTT (ratio 2.4, 1.3, 1, Ptrend=0.006). Haplotypic analysis using tagging SNPs did not improve the single SNP association values.
Keywords
ATP-Binding Cassette Transporters/*genetics
Area Under Curve
Cohort Studies
Genotype
HIV Protease Inhibitors/*pharmacology
HIV Seropositivity/drug therapy/genetics
Haplotypes
Humans
Leukocytes, Mononuclear/cytology
Mitochondrial Proteins/*genetics
Multidrug Resistance-Associated Proteins/*genetics
Nelfinavir/*pharmacology
Neoplasm Proteins/*genetics
P-Glycoprotein/*genetics
Pharmacogenetics/*methods
Phenotype
*Polymorphism, Genetic
Ribosomal Proteins/*genetics
Saccharomyces cerevisiae Proteins/*genetics
Variation (Genetics)
Pubmed
Web of science
Create date
25/01/2008 11:51
Last modification date
20/08/2019 16:22