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Mikko Niemi - One of the best experts on this subject based on the ideXlab platform.
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Enantiospecific Pharmacogenomics of Fluvastatin.
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Päivi Hirvensalo, Janne T. Backman, Aleksi Tornio, Mikko Neuvonen, Wilma Hanna-maria Kiander, Heidi Kidron, Maria Paile-hyvärinen, Tuija Tapaninen, Mikko NiemiAbstract:The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10-9 and P = 3.19 × 10-12 ). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10-8 ). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single-nucleotide variations may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.
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SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid
Pharmacogenetics and Genomics, 2015Co-Authors: Marja K. Pasanen, Pertti J. Neuvonen, Mikko Neuvonen, Mikko NiemiAbstract:Background and objective Organic anion transporting polypeptide 1B1 (OATP1B1) is an uptake transporter located at the sinusoidal membrane of human hepatocytes. This study aimed to investigate the effects of genetic polymorphism in the SLCO1B1 gene encoding OATP1B1 on the pharmacokinetics of simvastatin. Methods Four healthy volunteers with the homozygous SLCO1B1 c.521CC genotype, 12 with the heterozygous c.521TC genotype and 16 with the homozygous c.521TT genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of simvastatin. Plasma concentrations of simvastatin (inactive lactone) and its active metabolite simvastatin acid were measured for 12h. Results The AUC0–N of simvastatin acid was 120 and 221% higher in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TC and c.521TT (reference) genotypes, respectively (P<0.001). The Cmax of simvastatin acid was 162 and 200% higher in participants with the c.521CC genotype than in those with the c.521TC and c.521TTgenotypes (P<0.001). The Cmax of simvastatin acid occurred earlier in participants with the c.521CC and c.521TC genotypes than in those with the c.521TTgenotype (P<0.05). No association existed between the SLCO1B1 genotype and the elimination half-life of simvastatin acid. Moreover, no statistically significant association was seen between the SLCO1B1 genotype and the pharmacokinetics of simvastatin lactone. Conclusions SLCO1B1 polymorphism markedly affects the pharmacokinetics of active simvastatin acid, but has no significant effect on parent simvastatin. Raised plasma concentrations of simvastatin acid in patients carrying the SLCO1B1 c.521C variant allele may enhance the risk of systemic adverse effects during simvastatin treatment. In addition, reduced uptake of simvastatin acid by OATP1B1 into the liver in patients with the c.521C allele could reduce its cholesterol-lowering efficacy. Pharmacogenetics and Genomics 16:873–879 c 2006 Lippincott Williams & Wilkins.
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SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid.
Pharmacogenetics and genomics, 2015Co-Authors: Aleksi Tornio, Juha Vakkilainen, Janne T. Backman, Pertti J. Neuvonen, Mikko Neuvonen, Mikko NiemiAbstract:Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1 gene) is a hepatic uptake transporter, and its genetic variability is associated with pharmacokinetics and muscle toxicity risk of simvastatin. We examined the possible effects of variations in the SLCO1B1 gene on the pharmacokinetics of lovastatin in a prospective genotype panel study. Seven healthy volunteers with the SLCO1B1*1B/*1B genotype, five with the SLCO1B1*5/*15 or *15/*15 genotype, and 15 with the SLCO1B1*1A/*1A genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of lovastatin. Plasma concentrations of lovastatin (inactive lactone) and its active metabolite lovastatin acid were measured up to 24 h. In the SLCO1B1*5/*15 or *15/*15 genotype group, the geometric mean Cmax and AUC0-24 of lovastatin acid were 340 and 286% of the corresponding values in the SLCO1B1*1A/*1A (reference) genotype group (P<0.005). In contrast, the AUC0-24 of lovastatin acid in the SLCO1B1*1B/*1B genotype group was only 68% of that in the reference genotype group (P=0.03). No statistically significant association was observed between the SLCO1B1 genotype and the pharmacokinetics of lovastatin lactone. SLCO1B1*5/*15 and *15/*15 genotypes markedly increase the exposure to active lovastatin acid, but have no significant effect on lovastatin lactone, similar to their effects on simvastatin and simvastatin acid. Accordingly, it is probable that the risk of muscle toxicity during lovastatin treatment is increased in individuals carrying the SLCO1B1*5 or *15 allele. The SLCO1B1*1B/*1B genotype is associated with reduced lovastatin acid concentrations, consistent with enhanced hepatic uptake.
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No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid
European Journal of Clinical Pharmacology, 2011Co-Authors: Xiaoqiang Xiang, Juha Vakkilainen, Janne T. Backman, Pertti J. Neuvonen, Mikko NiemiAbstract:Purpose To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers. Methods In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1 * 1A /* 1A genotype, seven with the * 1B /* 1B genotype, and five with the * 15 /* 15 or * 5 /* 15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography–tandem mass spectrometry. Results The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC_0-12) in subjects with the SLCO1B1 * 1B /* 1B genotype and in subjects with the SLCO1B1 * 15 /* 15 or * 5 /* 15 genotype to the AUC_0-12 in subjects with the SLCO1B1 * 1A /* 1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC_0-24 of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC_0-24 of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC_0-24 of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold ( P
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SLCO1B1 polymorphism and oral antidiabetic drugs.
Basic & clinical pharmacology & toxicology, 2010Co-Authors: Annikka Kalliokoski, Pertti J. Neuvonen, Mikko NiemiAbstract:Abstract: Organic anion-transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1) is an influx transporter expressed on the sinusoidal membrane of human hepatocytes, where it mediates the uptake of its substrates from blood into liver. In vitro, the SLCO1B1 c.521T > C (p.Val174Ala) single-nucleotide polymorphism (SNP) has been associated with reduced and the c.388A > G (p.Asn130Asp) SNP with both enhanced and reduced transport activity of OATP1B1. In vivo in humans, the c.521C allele (present in SLCO1B1*5 and *15 haplotypes) is associated with decreased hepatic uptake and increased plasma concentrations of several OATP1B1 substrates. The SLCO1B1*1B (c.388G-c.521T) haplotype is associated with enhanced hepatic uptake and decreased plasma concentrations of some OATP1B1 substrates. The SLCO1B1 c.521CC genotype has been associated with an about 60-190% increased, and the SLCO1B1*1B/*1B genotype with an about 30% decreased area under the plasma concentration-time curve of repaglinide. Moreover, SLCO1B1 polymorphism can affect the extent of interaction between OATP1B1 inhibitors and repaglinide. Accordingly, SLCO1B1 genotyping may help in choosing the optimal starting dose of repaglinide. In Chinese individuals, the SLCO1B1 c.521C allele has been associated with increased plasma concentrations of nateglinide, but the association could not be replicated in Caucasians. SLCO1B1 genotype has had no effect on the pharmacokinetics of rosiglitazone, pioglitazone or their metabolites. The hepatic uptake of metformin is mediated by organic cation transporters 1 and 3, and the liver is not important for the elimination or action of the dipeptidylpeptidase 4 inhibitors sitagliptin, vildagliptin and saxagliptin. Therefore, SLCO1B1 polymorphism unlikely affects the response to these antidiabetics. Possible effects of SLCO1B1 polymorphism on sulfonylureas remain to be investigated.
Janne T. Backman - One of the best experts on this subject based on the ideXlab platform.
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Enantiospecific Pharmacogenomics of Fluvastatin.
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Päivi Hirvensalo, Janne T. Backman, Aleksi Tornio, Mikko Neuvonen, Wilma Hanna-maria Kiander, Heidi Kidron, Maria Paile-hyvärinen, Tuija Tapaninen, Mikko NiemiAbstract:The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10-9 and P = 3.19 × 10-12 ). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10-8 ). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single-nucleotide variations may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.
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SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid.
Pharmacogenetics and genomics, 2015Co-Authors: Aleksi Tornio, Juha Vakkilainen, Janne T. Backman, Pertti J. Neuvonen, Mikko Neuvonen, Mikko NiemiAbstract:Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1 gene) is a hepatic uptake transporter, and its genetic variability is associated with pharmacokinetics and muscle toxicity risk of simvastatin. We examined the possible effects of variations in the SLCO1B1 gene on the pharmacokinetics of lovastatin in a prospective genotype panel study. Seven healthy volunteers with the SLCO1B1*1B/*1B genotype, five with the SLCO1B1*5/*15 or *15/*15 genotype, and 15 with the SLCO1B1*1A/*1A genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of lovastatin. Plasma concentrations of lovastatin (inactive lactone) and its active metabolite lovastatin acid were measured up to 24 h. In the SLCO1B1*5/*15 or *15/*15 genotype group, the geometric mean Cmax and AUC0-24 of lovastatin acid were 340 and 286% of the corresponding values in the SLCO1B1*1A/*1A (reference) genotype group (P<0.005). In contrast, the AUC0-24 of lovastatin acid in the SLCO1B1*1B/*1B genotype group was only 68% of that in the reference genotype group (P=0.03). No statistically significant association was observed between the SLCO1B1 genotype and the pharmacokinetics of lovastatin lactone. SLCO1B1*5/*15 and *15/*15 genotypes markedly increase the exposure to active lovastatin acid, but have no significant effect on lovastatin lactone, similar to their effects on simvastatin and simvastatin acid. Accordingly, it is probable that the risk of muscle toxicity during lovastatin treatment is increased in individuals carrying the SLCO1B1*5 or *15 allele. The SLCO1B1*1B/*1B genotype is associated with reduced lovastatin acid concentrations, consistent with enhanced hepatic uptake.
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No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid
European Journal of Clinical Pharmacology, 2011Co-Authors: Xiaoqiang Xiang, Juha Vakkilainen, Janne T. Backman, Pertti J. Neuvonen, Mikko NiemiAbstract:Purpose To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers. Methods In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1 * 1A /* 1A genotype, seven with the * 1B /* 1B genotype, and five with the * 15 /* 15 or * 5 /* 15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography–tandem mass spectrometry. Results The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC_0-12) in subjects with the SLCO1B1 * 1B /* 1B genotype and in subjects with the SLCO1B1 * 15 /* 15 or * 5 /* 15 genotype to the AUC_0-12 in subjects with the SLCO1B1 * 1A /* 1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC_0-24 of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC_0-24 of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC_0-24 of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold ( P
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effects of the SLCO1B1 1b haplotype on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide
Pharmacogenetics and Genomics, 2008Co-Authors: Annikka Kalliokoski, Janne T. Backman, Pertti J. Neuvonen, Mikko NiemiAbstract:ObjectiveOrganic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, is an influx transporter expressed on the sinusoidal membrane of human hepatocytes. The aim of this study was to investigate whether the SLCO1B1*1B haplotype affects the pharmacokinetics and pharmacodynamics of repagl
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Effects of the SLCO1B1*1B haplotype on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide
Pharmacogenetics and genomics, 2008Co-Authors: Annikka Kalliokoski, Janne T. Backman, Pertti J. Neuvonen, Mikko NiemiAbstract:ObjectiveOrganic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, is an influx transporter expressed on the sinusoidal membrane of human hepatocytes. The aim of this study was to investigate whether the SLCO1B1*1B haplotype affects the pharmacokinetics and pharmacodynamics of repagl
Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid
Pharmacogenetics and Genomics, 2015Co-Authors: Marja K. Pasanen, Pertti J. Neuvonen, Mikko Neuvonen, Mikko NiemiAbstract:Background and objective Organic anion transporting polypeptide 1B1 (OATP1B1) is an uptake transporter located at the sinusoidal membrane of human hepatocytes. This study aimed to investigate the effects of genetic polymorphism in the SLCO1B1 gene encoding OATP1B1 on the pharmacokinetics of simvastatin. Methods Four healthy volunteers with the homozygous SLCO1B1 c.521CC genotype, 12 with the heterozygous c.521TC genotype and 16 with the homozygous c.521TT genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of simvastatin. Plasma concentrations of simvastatin (inactive lactone) and its active metabolite simvastatin acid were measured for 12h. Results The AUC0–N of simvastatin acid was 120 and 221% higher in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TC and c.521TT (reference) genotypes, respectively (P<0.001). The Cmax of simvastatin acid was 162 and 200% higher in participants with the c.521CC genotype than in those with the c.521TC and c.521TTgenotypes (P<0.001). The Cmax of simvastatin acid occurred earlier in participants with the c.521CC and c.521TC genotypes than in those with the c.521TTgenotype (P<0.05). No association existed between the SLCO1B1 genotype and the elimination half-life of simvastatin acid. Moreover, no statistically significant association was seen between the SLCO1B1 genotype and the pharmacokinetics of simvastatin lactone. Conclusions SLCO1B1 polymorphism markedly affects the pharmacokinetics of active simvastatin acid, but has no significant effect on parent simvastatin. Raised plasma concentrations of simvastatin acid in patients carrying the SLCO1B1 c.521C variant allele may enhance the risk of systemic adverse effects during simvastatin treatment. In addition, reduced uptake of simvastatin acid by OATP1B1 into the liver in patients with the c.521C allele could reduce its cholesterol-lowering efficacy. Pharmacogenetics and Genomics 16:873–879 c 2006 Lippincott Williams & Wilkins.
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SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid.
Pharmacogenetics and genomics, 2015Co-Authors: Aleksi Tornio, Juha Vakkilainen, Janne T. Backman, Pertti J. Neuvonen, Mikko Neuvonen, Mikko NiemiAbstract:Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1 gene) is a hepatic uptake transporter, and its genetic variability is associated with pharmacokinetics and muscle toxicity risk of simvastatin. We examined the possible effects of variations in the SLCO1B1 gene on the pharmacokinetics of lovastatin in a prospective genotype panel study. Seven healthy volunteers with the SLCO1B1*1B/*1B genotype, five with the SLCO1B1*5/*15 or *15/*15 genotype, and 15 with the SLCO1B1*1A/*1A genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of lovastatin. Plasma concentrations of lovastatin (inactive lactone) and its active metabolite lovastatin acid were measured up to 24 h. In the SLCO1B1*5/*15 or *15/*15 genotype group, the geometric mean Cmax and AUC0-24 of lovastatin acid were 340 and 286% of the corresponding values in the SLCO1B1*1A/*1A (reference) genotype group (P<0.005). In contrast, the AUC0-24 of lovastatin acid in the SLCO1B1*1B/*1B genotype group was only 68% of that in the reference genotype group (P=0.03). No statistically significant association was observed between the SLCO1B1 genotype and the pharmacokinetics of lovastatin lactone. SLCO1B1*5/*15 and *15/*15 genotypes markedly increase the exposure to active lovastatin acid, but have no significant effect on lovastatin lactone, similar to their effects on simvastatin and simvastatin acid. Accordingly, it is probable that the risk of muscle toxicity during lovastatin treatment is increased in individuals carrying the SLCO1B1*5 or *15 allele. The SLCO1B1*1B/*1B genotype is associated with reduced lovastatin acid concentrations, consistent with enhanced hepatic uptake.
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No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid
European Journal of Clinical Pharmacology, 2011Co-Authors: Xiaoqiang Xiang, Juha Vakkilainen, Janne T. Backman, Pertti J. Neuvonen, Mikko NiemiAbstract:Purpose To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers. Methods In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1 * 1A /* 1A genotype, seven with the * 1B /* 1B genotype, and five with the * 15 /* 15 or * 5 /* 15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography–tandem mass spectrometry. Results The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC_0-12) in subjects with the SLCO1B1 * 1B /* 1B genotype and in subjects with the SLCO1B1 * 15 /* 15 or * 5 /* 15 genotype to the AUC_0-12 in subjects with the SLCO1B1 * 1A /* 1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC_0-24 of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC_0-24 of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC_0-24 of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold ( P
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SLCO1B1 polymorphism and oral antidiabetic drugs.
Basic & clinical pharmacology & toxicology, 2010Co-Authors: Annikka Kalliokoski, Pertti J. Neuvonen, Mikko NiemiAbstract:Abstract: Organic anion-transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1) is an influx transporter expressed on the sinusoidal membrane of human hepatocytes, where it mediates the uptake of its substrates from blood into liver. In vitro, the SLCO1B1 c.521T > C (p.Val174Ala) single-nucleotide polymorphism (SNP) has been associated with reduced and the c.388A > G (p.Asn130Asp) SNP with both enhanced and reduced transport activity of OATP1B1. In vivo in humans, the c.521C allele (present in SLCO1B1*5 and *15 haplotypes) is associated with decreased hepatic uptake and increased plasma concentrations of several OATP1B1 substrates. The SLCO1B1*1B (c.388G-c.521T) haplotype is associated with enhanced hepatic uptake and decreased plasma concentrations of some OATP1B1 substrates. The SLCO1B1 c.521CC genotype has been associated with an about 60-190% increased, and the SLCO1B1*1B/*1B genotype with an about 30% decreased area under the plasma concentration-time curve of repaglinide. Moreover, SLCO1B1 polymorphism can affect the extent of interaction between OATP1B1 inhibitors and repaglinide. Accordingly, SLCO1B1 genotyping may help in choosing the optimal starting dose of repaglinide. In Chinese individuals, the SLCO1B1 c.521C allele has been associated with increased plasma concentrations of nateglinide, but the association could not be replicated in Caucasians. SLCO1B1 genotype has had no effect on the pharmacokinetics of rosiglitazone, pioglitazone or their metabolites. The hepatic uptake of metformin is mediated by organic cation transporters 1 and 3, and the liver is not important for the elimination or action of the dipeptidylpeptidase 4 inhibitors sitagliptin, vildagliptin and saxagliptin. Therefore, SLCO1B1 polymorphism unlikely affects the response to these antidiabetics. Possible effects of SLCO1B1 polymorphism on sulfonylureas remain to be investigated.
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the effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range
British Journal of Clinical Pharmacology, 2008Co-Authors: Annikka Kalliokoski, Pertti J. Neuvonen, Mikko Neuvonen, Mikko NiemiAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Organic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes. • A common single nucleotide polymorphism, c.521TC (p.Val174Ala), of the SLCO1B1 gene has been associated with increased plasma repaglinide concentrations in healthy volunteers. • Previous studies at low repaglinide doses have suggested that the effect of SLCO1B1 c.521TC polymorphism on the pharmacokinetics of repaglinide could be dose-dependent. WHAT THIS STUDY ADDS • Repaglinide peak plasma concentration and area under the plasma concentration–time curve increased linearly along with repaglinide dose ranging from 0.25 to 2 mg in both the predominant c.521TT and rare c.521CC genotype group. • The effect of SLCO1B1 c.521TC polymorphism on repaglinide pharmacokinetics persists over a wide dose range. AIMS To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521TC (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent. METHODS Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of ≥1 week. RESULTS The mean area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P ≤ 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC0–∞ increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype. CONCLUSIONS The effect of SLCO1B1 c.521TC polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.
Richard Hockett - One of the best experts on this subject based on the ideXlab platform.
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genetic variation in metabolizing enzyme and transporter genes comprehensive assessment in 3 major east asian subpopulations with comparison to caucasians and africans
The Journal of Clinical Pharmacology, 2010Co-Authors: Mark W Farmen, Carmen M Dumaual, Reuben Kirobi Njau, Choo Hua Teng, Brian A Moser, Sandra L Close, Stephen D Wise, Shin Irie, Richard HockettAbstract:The advent of high-throughput technologies has proven valuable in the assessment of genetic differences and their effects on drug activation, metabolism, disposition, and transport. However, most studies to date have focused on a small number of genes or few alleles, some of which are rare and therefore observed infrequently or lacked rigorous ethnic characterization, thus reducing the ability to extrapolate within and among populations. In this study, the authors comprehensively assessed the allele frequencies of 165 variants comprising 27 drug-metabolizing enzyme and transporter (DMET) genes from 2188 participants across 3 major ethnic populations: Caucasians, Africans, and East Asians. This sample size was sufficiently large to demonstrate genetic differences among these major ethnic groups while concomitantly confirming similarities among East Asian subpopulations (Korean, Han Chinese, and Japanese). A comprehensive presentation of allele and genotype frequencies is included in the online supplement, and 3 of the most widely studied cytochrome P450 (CYP) genes, CYP2D6, CYP2C19, and CYP2C9; 2 non-CYP enzymes, NAT1 and TMPT; and 2 transporter genes, SLCO1B1 and SLCO2B1, are presented herein according to ethnic classification.
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genetic variation in metabolizing enzyme and transporter genes comprehensive assessment in 3 major east asian subpopulations with comparison to caucasians and africans
The Journal of Clinical Pharmacology, 2010Co-Authors: Mark W Farmen, Carmen M Dumaual, Reuben Kirobi Njau, Choo Hua Teng, Brian A Moser, Sandra L Close, Stephen D Wise, Shin Irie, Richard HockettAbstract:The advent of high-throughput technologies has proven valuable in the assessment of genetic differences and their effects on drug activation, metabolism, disposition, and transport. However, most studies to date have focused on a small number of genes or few alleles, some of which are rare and therefore observed infrequently or lacked rigorous ethnic characterization, thus reducing the ability to extrapolate within and among populations. In this study, the authors comprehensively assessed the allele frequencies of 165 variants comprising 27 drug-metabolizing enzyme and transporter (DMET) genes from 2188 participants across 3 major ethnic populations: Caucasians, Africans, and East Asians. This sample size was sufficiently large to demonstrate genetic differences among these major ethnic groups while concomitantly confirming similarities among East Asian subpopulations (Korean, Han Chinese, and Japanese). A comprehensive presentation of allele and genotype frequencies is included in the online supplement, and 3 of the most widely studied cytochrome P450 (CYP) genes, CYP2D6, CYP2C19, and CYP2C9; 2 non-CYP enzymes, NAT1 and TMPT; and 2 transporter genes, SLCO1B1 and SLCO2B1, are presented herein according to ethnic classification.
Shin Irie - One of the best experts on this subject based on the ideXlab platform.
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genetic variation in metabolizing enzyme and transporter genes comprehensive assessment in 3 major east asian subpopulations with comparison to caucasians and africans
The Journal of Clinical Pharmacology, 2010Co-Authors: Mark W Farmen, Carmen M Dumaual, Reuben Kirobi Njau, Choo Hua Teng, Brian A Moser, Sandra L Close, Stephen D Wise, Shin Irie, Richard HockettAbstract:The advent of high-throughput technologies has proven valuable in the assessment of genetic differences and their effects on drug activation, metabolism, disposition, and transport. However, most studies to date have focused on a small number of genes or few alleles, some of which are rare and therefore observed infrequently or lacked rigorous ethnic characterization, thus reducing the ability to extrapolate within and among populations. In this study, the authors comprehensively assessed the allele frequencies of 165 variants comprising 27 drug-metabolizing enzyme and transporter (DMET) genes from 2188 participants across 3 major ethnic populations: Caucasians, Africans, and East Asians. This sample size was sufficiently large to demonstrate genetic differences among these major ethnic groups while concomitantly confirming similarities among East Asian subpopulations (Korean, Han Chinese, and Japanese). A comprehensive presentation of allele and genotype frequencies is included in the online supplement, and 3 of the most widely studied cytochrome P450 (CYP) genes, CYP2D6, CYP2C19, and CYP2C9; 2 non-CYP enzymes, NAT1 and TMPT; and 2 transporter genes, SLCO1B1 and SLCO2B1, are presented herein according to ethnic classification.
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genetic variation in metabolizing enzyme and transporter genes comprehensive assessment in 3 major east asian subpopulations with comparison to caucasians and africans
The Journal of Clinical Pharmacology, 2010Co-Authors: Mark W Farmen, Carmen M Dumaual, Reuben Kirobi Njau, Choo Hua Teng, Brian A Moser, Sandra L Close, Stephen D Wise, Shin Irie, Richard HockettAbstract:The advent of high-throughput technologies has proven valuable in the assessment of genetic differences and their effects on drug activation, metabolism, disposition, and transport. However, most studies to date have focused on a small number of genes or few alleles, some of which are rare and therefore observed infrequently or lacked rigorous ethnic characterization, thus reducing the ability to extrapolate within and among populations. In this study, the authors comprehensively assessed the allele frequencies of 165 variants comprising 27 drug-metabolizing enzyme and transporter (DMET) genes from 2188 participants across 3 major ethnic populations: Caucasians, Africans, and East Asians. This sample size was sufficiently large to demonstrate genetic differences among these major ethnic groups while concomitantly confirming similarities among East Asian subpopulations (Korean, Han Chinese, and Japanese). A comprehensive presentation of allele and genotype frequencies is included in the online supplement, and 3 of the most widely studied cytochrome P450 (CYP) genes, CYP2D6, CYP2C19, and CYP2C9; 2 non-CYP enzymes, NAT1 and TMPT; and 2 transporter genes, SLCO1B1 and SLCO2B1, are presented herein according to ethnic classification.
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SLCO1B1 oatp1b1 an uptake transporter and abcg2 bcrp an efflux transporter variant alleles and pharmacokinetics of pitavastatin in healthy volunteers
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Ichiro Ieiri, S Suwannakul, Kazuya Maeda, H Uchimaru, K Hashimoto, Miyuki Kimura, H Fujino, Masaru Hirano, Hiroyuki Kusuhara, Shin IrieAbstract:To investigate the contribution of genetic polymorphisms of SLCO1B1 and ABCG2 to the pharmacokinetics of a dual substrate, pitavastatin, 2 mg of pitavastatin was administered to 38 healthy volunteers and pharmacokinetic parameters were compared among the following groups: 421C/C(*)1b/(*)1b (group 1), 421C/C(*)1b/(*)15 (group 2), 421C/C(*)15/(*)15 and 421C/A(*)15/(*)15 (group 3), 421C/A(*)1b/(*)1b (group 4), 421A/A(*)1b/(*)1b (group 5), and 421C/A(*)1b/(*)15 (group 6). In SLCO1B1, pitavastatin area under plasma concentration-time curve from 0 to 24 h (AUC(0-24)) for groups 1, 2, and 3 was 81.1+/-18.1, 144+/-32, and 250+/-57 ng h/ml, respectively, with significant differences among all three groups. In contrast to SLCO1B1, AUC(0-24) in groups 1, 4, and 5 was 81.1+/-18.1, 96.7+/-35.4, and 78.2+/-8.2 ng h/ml, respectively. Although the SLCO1B1 polymorphism was found to have a significant effect on the pharmacokinetics of pitavastatin, a nonsynonymous ABCG2 variant, 421C>A, did not appear to be associated with the altered pharmacokinetics of pitavastatin.