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Mikko Niemi - 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, 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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Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1
Genome Medicine, 2013Co-Authors: Anne T Nies, Mikko Niemi, Oliver Burk, Stefan Winter, Ulrich M Zanger, Bruno Stieger, Matthias Schwab, Elke SchaeffelerAbstract:Background Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1 ) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates. Methods Expression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin ( n = 82). Results Expression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A > G (rs2306283) even after correction for multiple testing ( P = 0.00034). This held true for haplotypes harboring c.388A > G but not the functional variant c.521T > C (rs4149056) associated with statin-related myopathy. c.388A > G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression. Conclusions Our results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A > G is the major determinant with additional consequences on atorvastatin plasma levels.
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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, 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.
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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, 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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Different Effects of SLCO1B1 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Repaglinide and Nateglinide
Journal of clinical pharmacology, 2008Co-Authors: Annikka Kalliokoski, Mikko NiemiAbstract:Thirty-two healthy volunteers with different SLCO1B1 genotypes ingested a 0.5-mg dose of repaglinide and 60-mg dose of nateglinide with a washout period of 1 week. Participants with SLCO1B1 c.521CC genotype (n = 4) had a 59% (P = 0.001) or 72% (P C polymorphism.
Ichiro Ieiri - One of the best experts on this subject based on the ideXlab platform.
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small dosing clinical study pharmacokinetic pharmacogenomic SLCO2B1 and abcg2 and interaction atorvastatin and grapefruit juice profiles of 5 probes for oatp2b1 and bcrp
Journal of Pharmaceutical Sciences, 2017Co-Authors: Yushi Kashihara, Shin Irie, Kazuya Maeda, Ichiro Ieiri, Miyuki Kimura, Takeshi Hirota, Takashi Yoshikado, Masato Fukae, Shunji Matsuki, Noritomo IzumiAbstract:The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 μg sulfasalazine, 250 μg rosuvastatin, 300 μg glibenclamide, 1200 μg celiprolol, and 600 μg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.
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Apple juice greatly reduces systemic exposure to atenolol
British journal of clinical pharmacology, 2012Co-Authors: Hyewon Jeon, Ichiro Ieiri, In-jin Jang, Seung Hwan Lee, Kyoichi Ohashi, Tsutomu Kotegawa, Joo Youn Cho, Seo Hyun Yoon, Sang-goo ShinAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Atenolol is an antihypertensive drug, of which negligible amounts are metabolized. • Fruit juices may decrease the oral absorption of drugs by inhibiting intestinal drug transporters, as demonstrated in vitro and in vivo. WHAT THIS STUDY ADDS • The pharmacokinetic characteristics of atenolol were determined according to the SLCO2B1 genotype after apple juice administration in healthy Korean volunteers. • Apple juice ingestion markedly reduced the systemic exposure to atenolol, but genetic variations in SLCO2B1 were unlikely to contribute substantial variability to the pharmacokinetics of atenolol. AIM Fruit juice reduces the plasma concentrations of several β-adrenoceptor blockers, likely by inhibiting OATP2B1-mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol. METHODS Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n= 6) and *3/*3 (n= 6)) were enrolled in this study. In a three-phase, one-sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice. RESULTS Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,tlast). In this study, the PK parameters of atenolol responded in a dose-dependent manner to apple juice. CONCLUSIONS Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457C>T had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.
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microdosing clinical study pharmacokinetic pharmacogenomic SLCO2B1 and interaction grapefruit juice profiles of celiprolol following the oral microdose and therapeutic dose
The Journal of Clinical Pharmacology, 2012Co-Authors: Ichiro Ieiri, Shin Irie, Kazuya Maeda, Miyuki Kimura, Yohei Doi, Tomohiro Sasaki, Takeshi Hirota, Takeshi Chiyoda, Mayuko Miyagawa, Kazuhide IwasakiAbstract:The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.
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quantitative population pharmacokinetic analysis of pravastatin using an enterohepatic circulation model combined with pharmacogenomic information on slco1b1 and abcc2 polymorphisms
The Journal of Clinical Pharmacology, 2009Co-Authors: Takafumi Ide, Kazuya Maeda, Tomohiro Sasaki, Shun Higuchi, Yuichi Sugiyama, Ichiro IeiriAbstract:The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 6 36 blood samples from 5 7 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1*15 significantly influenced relative bioavailability (F rel ); F rel was increased 1.50- and 1.95-fold in participants heterozygous and homozygous, respectively, for the * 15 allele in comparison with participants without the allele. No ABCC2 polymorphism was identified as a potential covariate for pravastatin. The bootstrap analysis indicated that the PK profile of pravastatin was adequately described by the proposed PPK model. SLCO1B1*15 has a significant effect on F rel , indicating that OATP1B1 is one of the determinants of systemic exposure to pravastatin.
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life threatening toxicities in a patient with ugt1a1 6 28 and slco1b1 15 15 genotypes after irinotecan based chemotherapy
Cancer Chemotherapy and Pharmacology, 2009Co-Authors: Hiroshi Takane, Tomohiro Sasaki, Kenji Otsubo, Shun Higuchi, Katsuyuki Kawamoto, Kuniaki Moriki, Hiroya Kitano, Ichiro IeiriAbstract:Introduction To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes.
Shin Irie - One of the best experts on this subject based on the ideXlab platform.
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small dosing clinical study pharmacokinetic pharmacogenomic SLCO2B1 and abcg2 and interaction atorvastatin and grapefruit juice profiles of 5 probes for oatp2b1 and bcrp
Journal of Pharmaceutical Sciences, 2017Co-Authors: Yushi Kashihara, Shin Irie, Kazuya Maeda, Ichiro Ieiri, Miyuki Kimura, Takeshi Hirota, Takashi Yoshikado, Masato Fukae, Shunji Matsuki, Noritomo IzumiAbstract:The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 μg sulfasalazine, 250 μg rosuvastatin, 300 μg glibenclamide, 1200 μg celiprolol, and 600 μg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.
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microdosing clinical study pharmacokinetic pharmacogenomic SLCO2B1 and interaction grapefruit juice profiles of celiprolol following the oral microdose and therapeutic dose
The Journal of Clinical Pharmacology, 2012Co-Authors: Ichiro Ieiri, Shin Irie, Kazuya Maeda, Miyuki Kimura, Yohei Doi, Tomohiro Sasaki, Takeshi Hirota, Takeshi Chiyoda, Mayuko Miyagawa, Kazuhide IwasakiAbstract:The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.
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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, Kazuya Maeda, Masaru Hirano, Hiroyuki Kusuhara, S Suwannakul, H Uchimaru, K Hashimoto, Miyuki Kimura, H Fujino, 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.
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.
Janne T. Backman - One of the best experts on this subject based on the ideXlab platform.
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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, 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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Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population.
European Journal of Clinical Pharmacology, 2006Co-Authors: Marja K. Pasanen, Janne T. Backman, Mikko NiemiAbstract:Objective Organic anion transporting polypeptide 1B1 (OATP1B1) is a drug uptake transporter located at the sinusoidal membrane of hepatocytes. Our aim was to establish high-throughput genotyping assays for the major known single nucleotide polymorphisms (SNP) in the SLCO1B1 gene encoding OATP1B1 and to investigate the frequencies of SNPs and haplotypes of SLCO1B1 in a large Caucasian population.
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polymorphic organic anion transporting polypeptide 1b1 is a major determinant of repaglinide pharmacokinetics
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Janne T. Backman, Mikko Niemi, Lauri I Kajosaari, Julian B S LeathartAbstract:Background and Objective A large interindividual variability exists in the plasma concentrations of repaglinide. Our aim was to investigate possible associations between the pharmacokinetics of repaglinide and single nucleotide polymorphisms (SNPs) in the genes encoding for the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1) and P-glycoprotein (MDR1, ABCB1) and the drug-metabolizing enzymes cytochrome P450 (CYP) 2C8 and CYP3A5. Methods A total of 56 healthy volunteers ingested a single 0.25-mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 hours. All subjects were genotyped for the −11187G>A and 521T>C SNPs in SLCO1B1 and the 3435C>T and 2677G>T/A SNPs in ABCB1, as well as for the CYP2C8*3 (416G>A, 1196A>G), CYP2C8*4 (792C>G), and CYP3A5*3 (6986A>G) alleles. Results The area under the plasma concentration-time curve from time 0 to infinity [AUC(0-∞)] and peak concentration in plasma (Cmax) of repaglinide varied 16.9-fold and 10.7-fold, respectively, between individual subjects. Multiple regression analyses indicated that the SLCO1B1 521T>C SNP and the CYP2C8*3 allele were independent predictors of the AUC(0-∞) and Cmax of repaglinide (adjusted multiple R2 = 45% and 36%, respectively). In subjects with the SLCO1B1 521CC genotype, the AUC(0-∞) of repaglinide was 107% and 188% higher, respectively, than in subjects with the SLCO1B1 521TC or 521TT (reference) genotype (P < .0001). In subjects with the CYP2C8*1/*3 genotype, the AUC(0-∞) and Cmax of repaglinide were 48% and 44% lower, respectively, than in those with the CYP2C8*1/*1 genotype (P < .05). The pharmacokinetics of repaglinide was not associated with the studied ABCB1 SNPs or the CYP3A5*3 allele. The elimination half-life of repaglinide was not associated with any SNP. Only the SLCO1B1 −11187GA genotype was significantly associated with an enhanced effect of repaglinide on blood glucose. Conclusions 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. Clinical Pharmacology & Therapeutics (2005) 77, 468–478; doi: 10.1016/j.clpt.2005.01.018
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high plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide c oatp c slco1b1
Pharmacogenetics, 2004Co-Authors: Mikko Niemi, Janne T. Backman, Mikko Neuvonen, Matthias Schwab, Elke Schaeffeler, Thomas Lang, Martin F Fromm, Carl Kyrklund, Reinhold Kerb, Pertti J NeuvonenAbstract: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.