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
Author(s)
Colombo  S., Soranzo  N., Rotger  M., Sprenger  R., Bleiber  G., Furrer  H., Buclin  T., Goldstein  D., Decosterd  L., Telenti  A.
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
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 10:51
Last modification date
20/08/2019 15:22
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