Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo.
OBJECTIVE
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.


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.
Colombo
Sara
S
Division of Clinical Pharmacology, University Hospital, Lausanne, Switzerland.
Soranzo
Nicole
N
Rotger
Margalida
M
Sprenger
Raimund
R
Bleiber
Gabriela
G
Furrer
Hansjakob
H
Buclin
Thierry
T
Goldstein
David
D
Décosterd
Laurent
L
Telenti
Amalio
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D019540:Area Under Curve; D015331:Cohort Studies; D014644:Genetic Variation; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006679:HIV Seropositivity / Q000188:drug therapy / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D024101:Mitochondrial Proteins / Q000235:genetics*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D019888:Nelfinavir / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012269:Ribosomal Proteins / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017320:HIV Protease Inhibitors; D024101:Mitochondrial Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019888:Nelfinavir; D009363:Neoplasm Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C093947:MRP2 protein, S cerevisiae; C421109:multidrug resistance-associated protein 1