Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics

Niemi, Mikko; Backman, Janne T.; Kajosaari, Lauri I.; Leathart, Julian; Neuvonen, Mikko; Daly, Ann K.; Eichelbaum, Michel; Kivistö, Kari T.; Neuvonen, Pertti J.

doi:10.1016/j.clpt.2005.01.018

Cited by 333 publications

(288 citation statements)

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“…Initial in vitro studies for CYP2C8*3 suggested a lower activity, 31,32 but more recent studies in healthy volunteers have repeatedly demonstrated an increased metabolizing capacity for this allele. [33][34][35][36] In contrast, CYP2C8 haplotype C 35,41 and CYP3A5*3 37 confer a reduced activity. As the polymorphisms conferring a low metabolizing capacity were associated with protection, whereas the allele with increased activity showed a higher neurotoxicity (Figure 2), and the effects of these polymorphisms were independent, we incorporated them in a single prediction model (risk alleles: rs11572080 A, rs1113129 G and rs776746 G; Table 3).…”

Section: Discussionmentioning

confidence: 99%

“…For CYP2C8 several studies have demonstrated that CYP2C8*3 (R139K; K399R) exhibits an altered activity. 31-36 CYP2C8*4 (I264M) has not been associated with an altered enzyme activity, 33 but it encodes a common variant protein which might not have been sufficiently studied. Regarding CYP2C8 haplotypes B and C, represented by CYP2C8*1B (rs7909236) and rs1113129, 25 we recently showed that they conferred an increased and reduced activity, respectively.…”

Section: Patientsmentioning

confidence: 99%

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Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

et al. 2010

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Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele) ¼ 0.55; 95% confidence interval (CI) ¼ 0.34-0.89; P ¼ 0.014 and HR (per allele) ¼ 0.51; 95%CI ¼ 0.30-0.86; and P ¼ 0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele) ¼ 1.72; 95%CI ¼ 1.05-2.82; and P ¼ 0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR ¼ 1.64 (95% CI ¼ 1.26-2.14; P ¼ 0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

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Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

et al. 2010

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“…[4][5][6][7] Moreover, the 521C/C genotype has been associated with increased plasma concentrations of statins and glinides in human studies. [8][9][10] In SLCO1B3, several single-nucleotide polymorphisms (SNPs) have been identified in coding and noncoding regions. At least three nonsynonymous SNPs have been found so far, with 334T4G (S112A) and 699G4A (M233I) increasing transporter activity in vitro.…”

Section: Introductionmentioning

confidence: 99%

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

et al. 2012

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It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon-intron junctions and the 5 0 and 3 0 flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of X0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.

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“…Therefore, impaired function of OATP1B1 caused by genetic polymorphisms would greatly affect plasma concentrations of substrate drugs, which may result in decrease in efficacy of the drugs or in increase in the risk of development of adverse effects. For example, it has been reported that carriers of the single nucleotide polymorphism (SNP), c.521T4C (p.Val174Ala), OATP1B1*5 or *15, show increased plasma concentrations of pravastatin, 6-8 repaglinide 9 and simvastatin. 10 Severe toxicity after irinotecanbased chemotherapy for lung cancer has also been reported in a patient with a homozygote for the SLCO1B1*15 allele, which carries the SNP c.521T4C (p.Val174Ala).…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy

et al. 2009

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In the present study, we analyzed the function of a novel mutation (c.1628T4G, p.Leu543Trp) in the solute carrier organic anion transporter (SLCO) 1B1 gene, encoding organic anion transporting polypeptide (OATP) 1B1, which was identified in a patient with pravastatin-induced myopathy. OATP1B1 variants carrying the mutation (OATP1B1*1a þ c.1628T4G or *1b þ c.1628T4G) showed a reduced transporting activity toward typical substrates and pravastatin compared with the activity of the references (OATP1B1*1a or *1b). This was due to reduction in V max values of the variants, not due to change in their K m values. OATP1B1*1b þ c.1628T4G was normally expressed on the plasma membrane of HEK293 cells at the same level as that of OATP1B1*1b. Taken together, our results suggest that the mutation c.1628T4G (p.Leu543Trp) reduced the function of OATP1B1 probably due to decrease in turnover rate of one OATP1B1 molecule rather than impairment of protein sorting to the plasma membrane.

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Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics

Abstract: Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the pharmacokinetics of repaglinide. The effect of SLCO1B1 polymorphism on the pharmacokinetics of repaglinide may be clinically important.

Cited by 333 publications

References 39 publications

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy

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