title: High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1).
abstract: This study aimed to characterize possible relationships between polymorphisms in the drug transporter genes organic anion transporting polypeptide-C (OATP-C, SLCO1B1), OATP-B (SLCO2B1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and multidrug resistance transporter (MDR1, ABCB1) and the pharmacokinetics of pravastatin. We studied 41 healthy Caucasian volunteers who had previously participated in pharmacokinetic studies with pravastatin. Six volunteers had a very high pravastatin AUC value and were defined as outliers according to statistical criteria. The OATP-C gene was sequenced completely in all subjects, and they were also genotyped for selected single nucleotide polymorphisms (SNP) in the OATP-B, MDR1 and MRP2 genes. Of the six outliers, five were heterozygous for the OATP-C 521T>C (Val174Ala) SNP (allele frequency 42%) and three were heterozygous for a new SNP in the promoter region of OATP-C (-11187G>A, allele frequency 25%). Among the remaining 35 subjects, two were homozygous and six were heterozygous carriers of the 521T>C SNP (allele frequency 14%, P = 0.0384 versus outliers) and three were heterozygous carriers of the -11187G>A SNP (allele frequency 4%, P = 0.0380 versus outliers). In subjects with the -11187GA or 521TC genotype, the mean pravastatin AUC0-12 was 98% (P = 0.0061) or 106% (P = 0.0034) higher, respectively, compared to subjects with the reference genotype. These results were substantiated by haplotype analysis. In heterozygous carriers of *15B (containing the 388A>G and 521T>C variants), the mean pravastatin AUC0-12 was 93% (P = 0.024) higher compared to non-carriers and, in heterozygous carriers of *17 (containing the -11187G>A, 388A>G and 521T>C variants), it was 130% (P = 0.0053) higher compared to non-carriers. No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs.
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Thomas
authors.initials: T
authors.lastname: Lang
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.forename: Carl
authors.initials: C
authors.lastname: Kyrklund
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kerb
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Kari T
authors.initials: KT
authors.lastname: Kivistö
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D019540:Area Under Curve; D005091:Exons; D005260:Female; D005387:Finland; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood*; D007438:Introns; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017035:Pravastatin / Q000097:blood* / Q000493:pharmacokinetics; D012016:Reference Values
chemical_list: C000715087:ABCC2 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D017035:Pravastatin