Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics.
OBJECTIVE
Our aim was to investigate possible effects of sequence variations in ABCC2, encoding the multidrug resistance-associated protein 2 (MRP2), on the pharmacokinetics of the MRP2 substrate pravastatin.


METHODS
Deoxyribonucleic acid samples of 41 healthy volunteers, in whom SLCO1B1 single nucleotide polymorphisms (SNPs) and haplotypes had previously been found to be associated with increased plasma pravastatin concentrations, were investigated. Each study participant had ingested a single 40-mg dose of pravastatin followed by blood sampling for pharmacokinetic characterization in standardized conditions. The exons, exon-intron boundaries, promoter region and 3'-untranslated region of the ABCC2 gene of six individuals with the highest and six individuals with the lowest pravastatin area under the plasma concentration-time curve (AUC) values were sequenced.


RESULTS
Of the 26 sequence variations found, the synonymous c.1446C>G SNP was observed heterozygously in three (50%) of the six individuals with a low pravastatin AUC and in none (0%) of the six individuals with a high AUC (P=0.06 for allele frequency). The remaining 29 participants were then also genotyped for c.1446C>G, but none of them carried the SNP. In addition, the effect of c.1446C>G on MRP2 mRNA expression was investigated in 93 human liver samples. A multiple linear regression analysis in the 41 participants with pravastatin pharmacokinetic data indicated that the ABCC2 c.1446C>G SNP and the previously identified SLCO1B1 haplotype *17 were independent predictors of the AUC0-12 and Cmax of pravastatin (r=32 and 29%, respectively) (P<0.01). In the participants heterozygous for the ABCC2 c.1446C>G SNP (n=3), who were not carriers of the SLCO1B1*17 haplotype, the AUC0-12 and Cmax of pravastatin were 67 and 68% lower than in those carrying neither the SLCO1B1*17 haplotype nor the ABCC2 c.1446C>G SNP (n=35) (P<0.05). MRP2 mRNA expression was 95% higher in livers with the c.1446CG genotype (n=7) than in those with the c.1446CC genotype (n=86) (P<0.05).


CONCLUSIONS
These results support the idea that the ABCC2 c.1446C>G SNP is associated with reduced systemic exposure to pravastatin as a consequence of increased MRP2 expression. The underlying mechanism may involve either a modulating effect of the SNP on mRNA stability or linkage to other polymorphism(s) acting at the transcriptional level.
Niemi
Mikko
M
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. mikko.niemi@hus.fi
Arnold
Katja A
KA
Backman
Janne T
JT
Pasanen
Marja K
MK
Gödtel-Armbrust
Ute
U
Wojnowski
Leszek
L
Zanger
Ulrich M
UM
Neuvonen
Pertti J
PJ
Eichelbaum
Michel
M
Kivistö
Kari T
KT
Lang
Thomas
T
D002478:Cells, Cultured; D015870:Gene Expression; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins / Q000235:genetics*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000493:pharmacokinetics*
D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D017035:Pravastatin; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human