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Ieiri I.,Kyushu University | Doi Y.,Kyushu University | Maeda K.,University of Tokyo | Sasaki T.,Kyushu University | And 7 more authors.
Journal of Clinical Pharmacology | Year: 2012

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 AUC0-24 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. © 2012 The Author(s).

Ieiri I.,Kyushu University | Fukae M.,Kyushu University | Maeda K.,University of Tokyo | Ando Y.,Kyushu University | And 10 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2012

Objectives: To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide). Methods: A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS. Results: The AUC and t 1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC 0-12 ratio of lansoprazole in EMs and PMs was 1:3.3-4.3. Among test drugs, phenotypic measurements of lansoprazole accorded well with the CYP2C19 genotype at the microdose as well as therapeutic dose. Conclusions: The present study suggests that 1) the sampling strategy should be optimized according to pharmacokinetic profiles of the test drugs following oral microdosing, and 2) microdosing can be applied to the pharmacogenomic study of CYP-specific drugs. ©2012 Dustri-Verlag Dr. K. Feistle.

Man M.,Eli Lilly and Company | Farmen M.,Eli Lilly and Company | Dumaual C.,Eli Lilly and Company | Teng C.H.,National University of Singapore | And 7 more authors.
Journal of Clinical Pharmacology | Year: 2010

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. © 2010 The Author(s).

PubMed | Sumida Hospital, Kitasato University, Kyushu Clinical Pharmacology Research Clinic, Clinical Pharmacology Center and Keio University
Type: | Journal: Journal of pharmaceutical health care and sciences | Year: 2016

Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA.Ten polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3-UTR, reduced folate carrier 1 (RFC1) 80 and-43, folypolyglutamyl synthase (FPGS) 1994, -glutamyl hydrolase (GGH) 452 and-401, the ABC transporters (ABCB1 3435, ABCC2 IVS23+56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR).Comparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23+56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH-401T, ABCB1 3435T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1-43C and ABCC2 IVS23+56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients.The variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.

PubMed | Sumida Hospital, Kitasato University, Kyushu Clinical Pharmacology Research Clinic, Clinical Pharmacology Center and Keio University
Type: Journal Article | Journal: Journal of clinical pharmacology | Year: 2016

Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well known, but little is known about those differences in relation to therapeutic response. Reduced folate carrier-1 (RFC-1), folypolyformyl glutamate synthase (FPGS), and -glutamyl hydrolase (GGH) are important transporters and enzymes that convert methotrexate (MTX) in the body. This study investigated the sex differences in mRNA expression of RFC-1, FPGS, and GGH in 190 unrelated healthy Japanese people. The genotypes and mRNA expression were determined using the real-time PCR method. Significant differences between men and women were observed in RFC-1, FPGS, and GGH mRNA expression. The mRNA expression of FPGS and GGH was greater in women than that in men, but the expression of RFC-1 was less in the former than the latter. In stratified analysis by genotype, significant differences in sex-specific mRNA expression were observed in G/G of FPGS, C/C of GGH 452, and C/C of GGH -401. All showed greater mRNA expression in women than in men. In the 5 single-nucleotide polymorphisms RFC-1 80G>A, RFC-1 -43T>C, FPGS 1994G>A, GGH 452C>T, and GGH -401C>T examined, the FPGS 1994 G/G (1.46-fold), GGH 452 C/C (2.16-fold), and GGH -401 C/C (2.68-fold) genotypes showed significantly higher mRNA expression in women than in men. Healthy Japanese adults in this study showed sex-specific differences in mRNA expression that differed among RFC-1, FPGS, and GGH. Therefore, the relationship between genetic polymorphisms and mRNA expression including sex differences might contribute to the variation in the efficacy/toxicity of MTX in patients with RA.

He Y.-L.,Novartis | Ito H.,Novartis | Yamaguchi M.,Novartis | Terao S.,Novartis | And 3 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2012

Objective: To assess the effects of meal timing on the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin in Japanese patients with Type 2 diabetes. Methods: In this open-label, single-center crossover study, 12 Japanese patients with Type 2 diabetes were randomized to twice-daily vildagliptin 50 mg, administered 30 min before or immediately before breakfast and dinner for 7 days. After a 7-day washout period, patients received the other regimen. Blood samples were collected for the determination of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1) and glucose. Results: Vildagliptin absorption appeared slower when administered 30 min before rather than immediately before meals (t maxabsolute range: 1.00 - 2.00 h vs. 0.33 - 1.58 h). Vildagliptin C max and AUC 0-8 h were essentially the same irrespective of meal timing (geometric mean ratio: C max 1.08 (90% CI; 0.92 - 1.26); AUC 0-8 h 0.97 (90% CI; 0.91 - 1.05)). Meal timing did not affect pharmacodynamics; complete DPP-4 inhibition (> 90%) was sustained for 8 h post-dose, and plasma active glucagon-like peptide-1 levels increased 2 - 3-fold from baseline. Fasting plasma glucose (FPG) and postprandial plasma glucose (PPPG) reductions from baseline did not differ significantly with meal timing (30 min before vs. immediately before: FPG, -8.9 vs. -5.8 mg/dl; adjusted AUE 0-4 h, -67.0 vs. -51.0 mgxh/dl). Vildagliptin was well tolerated. Conclusions: Dosing 30 min or immediately before meals did not affect vildagliptin pharmacokinetics or pharmacodynamics in Japanese patients with Type 2 diabetes. ©2012 Dustri-Verlag Dr. K. Feistle.

Stockis A.,UCB Pharma | Watanabe S.,UCB Pharma | Rouits E.,UCB Pharma | Matsuguma K.,Kyushu Clinical Pharmacology Research Clinic | Irie S.,Kyushu Clinical Pharmacology Research Clinic
Drug Metabolism and Pharmacokinetics | Year: 2014

Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in phase 3 clinical development for epilepsy. A phase 1, single-center, randomized, double-blind, placebo-controlled, single (2.5-100 mg) and multiple (2.5-50 mg twice daily) rising oral dose study (N01209) was conducted to assess the adverse event profile and pharmacokinetics of brivaracetam in healthy Japanese men, and the influence of the cytochrome P450 (CYP) 2C19 genotype. Plasma and urine were collected serially for analysis of brivaracetam and its three main metabolites: acid, hydroxy and hydroxy acid. Overall, 79/80 randomized participants completed the study. Brivaracetam was generally well tolerated. After single- and multiple-dose administration, brivaracetam was rapidly absorbed, with dose-proportional pharmacokinetics over the dose ranges tested. Steady state was reached after 2 days of repeated dosing. Brivaracetam clearance (averaged across the five single dose levels) was reduced from 0.99 mL/min/kg in homozygous extensive metabolizers (EM; n = 10) to 0.81 mL/min/kg (-18%) in heterozygous EM (n = 17) and 0.70 mL/min/kg (-29%) in poor metabolizers (PM; n = 9). Exposure and urinary excretion of hydroxy metabolite were reduced 10-fold in PM participants, compared with EM participants. Results suggest that brivaracetam is hydroxylated by CYP2C19, but this pathway is minor compared with hydrolysis to the acid metabolite. Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX).

Ieiri I.,Kyushu University | Nishimura C.,Kyushu University | Maeda K.,University of Tokyo | Sasaki T.,Kyushu University | And 8 more authors.
Pharmacogenetics and Genomics | Year: 2011

Objectives: In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. Methods: Telmisartan was orally administered at MD condition (100 μg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. Results: No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. Conclusion: The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Sasaki T.,Kyushu University | Hirota T.,Kyushu University | Ryokai Y.,Kyushu University | Kobayashi D.,Kyushu University | And 4 more authors.
Drug Metabolism and Pharmacokinetics | Year: 2011

The present study was undertaken to identify genetic polymorphisms of multidrug resistanceassociatedprotein 3 (MRP3, gene name ABCC3), an ATP-binding cassette transporter that mediates thetransport of substrates across the basolateral membrane into the blood, and to investigate their effects onABCC3 expression and MRP3 function. We identified genetic polymorphisms of ABCC3 and evaluatedthe effects by (1) a luciferase reporter gene assay, (2) measuring mRNA levels, and (3) a humanpharmacogenomics study with 4-methylumbelliferone glucuronide (4-MUG). Overall, 61 genetic variantswere identified in three ethnic populations; of these variants 17 were novel (7 were non-synonymous:61Arg>Cys, 132Gln>Stop, 221Trp>Stop, 270His>Gln, 548Leu>Gln, 600Lys>Arg, and 1324Arg>His). However, these mutations occurred at very low frequencies (max. 4.7%). The observed allelefrequencies showed considerable inter-ethnic differences. The reporter gene assay indicated a significantreduction of transcriptional activity with the - 1767G>A allele compared to the wild-type allele; however, adecreased expression of ABCC3 mRNA was not detected in human liver samples. A human pharmacokineticstudy showed that the ABCC3 genotype in the promoter region was not associated with changes inthe pharmacokinetics of 4-MUG, a substrate of MRP3. This is the first study to assess the effects of ABCC3polymorphisms on human pharmacokinetics; however, further investigations are needed to complete thepicture. © 2011by the Japanese Society for the Study of Xenobiotics (JSSX).

Yoshimura E.,Fukuoka University | Kumahara H.,Nakamura Gakuen University | Tobina T.,Fukuoka University | Matono S.,Fukuoka University | And 8 more authors.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy | Year: 2011

Purpose: To evaluate the relationships between insulin sensitivity (IS), body fat accumulation, and aerobic capacity in middle- to older-aged Japanese participants with visceral adiposity. Participants and methods: Aerobic capacity was measured during an incremental ramp exercise test. Computed tomography was used to measure visceral (VFA) and subcutaneous (SFA) fat area, the fat in liver-to-spleen ratio (L/S), and low-density skeletal muscle area (LDMA). IS was assessed using euglycemic-hyperinsulinemic clamps. Results: A total of 11 males and 9 females, age 58 ± 9 years (mean ± standard deviation), body mass index 29 ± 4.1 kg/m2, and VFA 190 ± 53 cm2 participated in this study. In unadjusted models, VFA, LDMA, and L/S were significantly correlated with IS, which remained in adjusted models for LDMA and L/S, but not for VFA. In multiple stepwise regression analysis including sex, age, body fat, VFA, SFA, alcohol consumption, and aerobic capacity (oxygen uptake at the lactate threshold), L/S, and LDMA accounted for 70% of the total variance in IS. Percentage body fat and SFA, but not VFA, were significantly correlated with high molecular-weight adiponectin levels (r = 0.58, P < 0.01 and r = 0.54, P < 0.05, respectively). IS and L/S were significantly and negatively correlated with tumor necrosis factor-α (r = -0.67 and -0.63, respectively; both P < 0.01) and plasminogen activator inhibitor-1 (r = -0.58, P < 0.01 and -0.52, P < 0.05, respectively), whereas LDMA was not. Conclusion: These findings indicate that ectopic fat deposition in the liver and skeletal muscle may be associated with peripheral IS independently of body fat accumulation and aerobic capacity in middle- to older-aged Japanese individuals with visceral adiposity. Because of the small sample size, additional larger studies are needed to provide further insight into these preliminary findings. © 2011 Sibal et al.

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