Takeshi Hirota

Kyushu University, Hukuoka, Fukuoka, Japan

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Publications (32)85.16 Total impact

  • Takeshi Hirota · Ichiro Ieiri
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    ABSTRACT: Introduction: Lipid-lowering drugs, especially hydroxymethylglutaryl-CoA reductase inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic diseases. The benefits of statins are well documented. However, myotoxic side effects, which can sometimes be severe, including myopathy or rhabdomyolysis, have been associated with the use of statins. In some cases, this toxicity is associated with pharmacokinetic alterations. Potent inhibitors of CYP 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin is metabolized by CYP2C9, while pravastatin, rosuvastatin and pitavastatin are not susceptible to inhibition by any CYP. Areas covered: This review discusses the pharmacokinetic aspects of the drug-drug interaction with statins and genetic polymorphisms in CYPs, which are involved in the metabolism of statins, and highlights the importance of establishing a system utilizing electronic medical information practically to avoid adverse drug reactions. Expert opinion: An understanding of the mechanisms underlying statin interactions will help to minimize drug interactions and develop statins that are less prone to adverse interactions. Quantitatively analyzed information for the low-density lipoprotein cholesterol lowering effects of statin based on electronic medical records may be useful for avoiding the adverse effect of statins.
    Expert Opinion on Drug Metabolism &amp Toxicology 06/2015; 11(9):1-13. DOI:10.1517/17425255.2015.1056149 · 2.83 Impact Factor
  • British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12654 · 3.88 Impact Factor
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    ABSTRACT: Dubin–Johnson syndrome (DJS) is an autosomal recessive inherited disorder characterized by conjugated hyperbilirubinemia. Neonatal-onset DJS is rare. It is caused by dysfunction of adenosine triphosphate-binding cassette, sub-family C, member 2 (ABCC2). We found a novel compound heterozygous mutation of DJS-related gene: W709R (T2145C): a missense mutation in exon 17, and R768W (C2302T), a missense mutation in exon 18. Serum diglucuronosyl bilirubin/monoglucuronosyl bilirubin ratio was high. ABCC2 may excrete diglucuronosyl bilirubin preferentially over monoglucuronosyl bilirubin.
    Pediatrics International 10/2014; 56(5). DOI:10.1111/ped.12404 · 0.73 Impact Factor
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    ABSTRACT: Background: Interethnic differences in genetic polymorphism in genes encoding drug-metabolizing enzymes and transporters are one of the major factors that cause ethnic differences in drug response. This study aimed to investigate genetic polymorphisms in genes involved in drug metabolism, transport, and excretion among Korean, Japanese, and Chinese populations, the three major East Asian ethnic groups. Methods: The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese) using the Affymetrix Drug-Metabolizing Enzymes and Transporters Plus microarray. To compare allele or genotype frequencies in the high-dimensional data among the three East Asian ethnic groups, multiple testing, principal component analysis (PCA), and regularized multinomial logit model through least absolute shrinkage and selection operator were used. Results: On microarray analysis, 1071 of 1936 variants (>50% of markers) were found to be monomorphic. In a large number of genetic variants, the fixation index and Pearson's correlation coefficient of minor allele frequencies were less than 0.034 and greater than 0.95, respectively, among the three ethnic groups. PCA identified 47 genetic variants with multiple testing, but was unable to discriminate ethnic groups by the first three components. Multinomial least absolute shrinkage and selection operator analysis identified 269 genetic variants that showed different frequencies among the three ethnic groups. However, none of those variants distinguished between the three ethnic groups during subsequent PCA. Conclusion: Korean, Japanese, and Chinese populations are not pharmacogenetically distant from one another, at least with regard to drug disposition, metabolism, and elimination.
    Pharmacogenetics and Genomics 07/2014; 24(10). DOI:10.1097/FPC.0000000000000075 · 3.48 Impact Factor
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    ABSTRACT: This study was performed to identify genetic polymorphisms in multidrug and toxin extrusion 2-K (MATE2-K, SLC47A2), a proton/organic cation antiporter that plays a role in the transport of organic cations across the apical membrane in kidney epithelial cells into the urine, and to demonstrate their effects on MATE2-K functions in vitro. Four of the thirty single nucleotide polymorphisms (SNPs) we identified in three ethnic groups (Caucasian, African American, and Japanese) were novel [308C>G (P103R), c.487-8C>T, 818A>G (Y273C), and c.1018+14T>C]. The transport activities of the prototypical substrates, tetraethylammonium and metformin, for four nonsynonymous SNPs (P103R, P162L, G211V, and Y273C) were significantly different from those of the wild type. In particular, transport activity was higher in P103R than in the wild type, which is the first time elevated transport activity was demonstrated due to these coding SNPs. Kinetic analysis revealed that P103R had a higher Vmax value, while Y273C had a lower value than that in the wild type. Cell surface protein expression levels were higher for P103R than for the wild type, whereas Y273C expression was decreased. Immunofluorescence analysis revealed that the P103R protein was localized to the plasma membrane, whereas Y273C showed cytoplasmic localization. Therefore, the difference in transport activities between P103R and Y273C variants was suggested to be responsible for the different protein expression levels observed at the plasma membrane. Four nonsynonymous SNPs in this study showed relatively low allelic frequencies (0.5 to 2.1%), but these were associated with markedly reduced or increased MATE2-K function.
    Drug metabolism and disposition: the biological fate of chemicals 07/2014; 42(9). DOI:10.1124/dmd.114.056887 · 3.25 Impact Factor
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    ABSTRACT: AimsHMG-CoA reductase inhibitors are available for use in low-density lipoprotein-cholesterol (LDL-C) lowering therapy. The purposes of this study were to develop a population pharmacodynamic (PPD) model to describe the time course for the LDL-C lowering effects of statins and assess the efficacy of combination therapy based on electronic medical records.Methods Patient backgrounds, laboratory tests, and prescribed drugs were collected retrospectively from electronic medical records. Patients who received atorvastatin, pitavastatin, or rosuvastatin were enrolled. A physiological indirect response model was used to describe the changes observed in LDL-C levels. The PPD analysis was performed using NONMEM 7.2.0 with the first-order conditional estimation method with interaction (FOCE-INTER).ResultsAn indirect response Imax model, based on the 2863 LDL-C levels of 378 patients, successfully and quantitatively described the time course for the LDL-C lowering effects of three statins. The combination of ezetimibe, a cholesterol absorption inhibitor, decreased the LDL synthesis rate (Kin) by 10.9%. A simulation indicated that the combined treatment of ezetimibe with rosuvastatin (2.5 mg/day) led to superior clinical responses than those with high doses of rosuvastatin (5.0 mg/day) monotherapy, even in patients with higher baseline LDL-C levels prior to the treatment.ConclusionsA newly constructed PPD model supported previous evidence for the beneficial effects of ezetimibe combined with rosuvastatin. In addition, the established framework is expected to be applicable to other drugs without pharmacokinetic data in clinical practice.
    British Journal of Clinical Pharmacology 04/2014; 78(4). DOI:10.1111/bcp.12405 · 3.88 Impact Factor
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    ABSTRACT: MicroRNA (miRNA) are non-coding small RNA that regulate gene expression. MiR-328 is reported to influence breast cancer resistance protein (BCRP) expression in cancer cells. As a large inter-individual difference in BCRP levels is observed in various human tissues, the contribution of miR-328 to these differences is of interest. We hypothesized that DNA methylation in the miR-328 promoter region is responsible for the difference in miR-328 levels, leading to inter-individual variability in BCRP levels in human placenta. The association between placental miR-328 and BCRP levels was analyzed, and then DNA methylation in the miR-328 5'-flanking region and regulatory mechanisms causing inter-individual differences in miR-328 and BCRP levels were examined. MiR-328 expression was significantly correlated with BCRP mRNA (Rs = -0.560, P < 0.01) and protein (Rs = -0.730, P < 0.01) levels. It was also up-regulated by the demethylating agent 5-aza-2'-deoxycytidine in BCRP-expressing cells. Luciferase assays with differentially methylated reporter constructs indicated that methylation in the miR-328 5'-flanking region including a predicted CpG island remarkably decreased transcriptional activity compared to that in unmethylated constructs. We selected CCAAT/enhancer binding protein α (C/EBPα), located within the predicted CpG island, by in silico analysis. To elucidate the role of C/EBPα in miR-328 expression, a chromatin immunoprecipitation assay, promoter deletion analysis, and electrophoretic mobility shift assay (EMSA) were performed. C/EBPα-binding site-truncated constructs showed significantly decreased promoter activity, and EMSA indicated that the C/EBPα-binding sites were located in the CpG island. Finally, the methylation patterns of several CpG dinucleotides proximal to two C/EBPα-binding sites in the miR-328 5'-flanking region were correlated negatively with miR-328 levels, and positively with BCRP levels in human placental samples. These results suggest that methylation patterns in the miR-328 5'-flanking region are involved in the inter-individual difference in BCRP levels in human placenta.
    PLoS ONE 08/2013; 8(8):e72906. DOI:10.1371/journal.pone.0072906 · 3.23 Impact Factor
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    ABSTRACT: Thymidylate synthase (TYMS) is an important folate-dependent enzyme in DNA synthesis and an important target for cancer chemotherapy. High TYMS expression levels in tumors are generally associated with resistance to 5-fluorouracil (5-FU). The cause of the variability in TYMS expression is still not fully understood, however, only a small proportion of the TYMS expression can be explained by TYMS genetic polymorphisms. The purpose of this study is to identify novel microRNAs (miRNAs) which regulate the expression of TYMS and to determine whether miRNAs binding to the 3[prime]-untranslated region (UTR) of TYMS mRNA affect the proliferation of HeLa cells treated with 5-FU. An in silico search was performed to find potential binding sites of miRNAs in TYMS mRNA. The efficacy of predicted miRNAs at the 3[prime]-UTR of TYMS mRNA was evaluated using a dual-luciferase reporter assay. TYMS mRNA and protein expression in HeLa cells was quantified with real-time RT-PCR and Western blotting, respectively. The effects of miR-433 on cell proliferative activity were determined by WST-8 assay. The overexpression of miR-433 was associated with significantly decreased reporter activity in the plasmid containing the 3[prime]-UTR of TYMS mRNA (P < 0.01). The levels of TYMS mRNA and protein in HeLa cells were significantly decreased by the overexpression of miR-433 (P < 0.05). Furthermore, miR-433 increased inhibition of cell proliferation in HeLa cells treated with 5-FU at over 2.0 muM. The results indicate that miR-433 post-transcriptionally regulates the expression of TYMS mRNA and protein, and increases sensitivity to 5-FU in HeLa cells. This is the first report showing that a miRNA regulating TYMS expression has a significant impact on sensitivity to 5-FU treatment.
    BMC Cancer 08/2013; 13(1):369. DOI:10.1186/1471-2407-13-369 · 3.36 Impact Factor
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    ABSTRACT: We investigated the mechanisms of ritonavir-mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p-glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC-MS/MS methods. The mean plasma AUC(0-24) (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration-time curve (AUC)(0-24) ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01-.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A-mediated metabolism, and intestinal p-glycoprotein-mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.
    The Journal of Clinical Pharmacology 06/2013; 53(6):1-16. DOI:10.1002/jcph.62 · 2.48 Impact Factor
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    ABSTRACT: The aims of the presents study were to define inter-individual differences in response to methotrexate (MTX) through MTX polyglutamate (PG) levels in red blood cells (RBC) and MTX-related gene polymorphisms. A total of 145 rheumatoid arthritis patients were recruited. MTX-PG1-5 concentrations in RBC were measured, and 11 single nucleotide polymorphisms, all in MTX-related genes involved in the folate pathway, were analyzed. Disease activity was also assessed. There was no direct relationship between each MTX-PG concentration and the patient's disease condition, but detectability of MTX-PG5 was extracted as a candidate marker for response to MTX. When disease activity was compared between patients in which MTX-PG5 was detectable and undetectable, all indexes except visual analog scale (VAS) and C-reactive protein (CRP) were found to be significantly lower in the former patients. Reduced folate carrier 1 (RFC1) 80G>A was significantly associated with the detectability of MTX-PG5; detectability of MTX-PG5 was lower in patients with the A mutant allele. The present study suggests that detectability of MTX-PG5 in RBC is a possible biomarker for response to MTX, and the RFC1 80G>A mutation is associated with low detectability of MTX-PG5. Prospective studies with sufficient number of patients are needed to confirm the present findings.
    Drug Metabolism and Pharmacokinetics 04/2013; 28(5). DOI:10.2133/dmpk.DMPK-12-RG-128 · 2.57 Impact Factor
  • Takeshi Hirota · Shunsuke Eguchi · Ichiro Ieiri
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    ABSTRACT: Human cytochrome P450 (CYP) is a superfamily of hemoproteins which oxidize a number of endogenous compounds and xenobiotics. The human CYP2C subfamily consists of four members; CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 and CYP2C19 are important drug metabolizing enzymes and together metabolize approximately 20% of therapeutically used drugs. Forty two allelic variants for CYP2C9 and 34 for CYP2C19 have been reported. The frequencies of these variants show marked inter-ethnic variation. The functional consequences of genetic polymorphisms have been examined, and many studies have shown the clinical importance of these polymorphisms. Current evidence suggests that taking the genetically determined metabolic capacity of CYP2C9 and CYP2C19 into account has the potential to improve individual risk/benefit relationships. However, more prospective studies with clinical endpoints are needed before the paradigm of 'personalized medicine' based on the variants can be established. This review summarizes the currently available important information on this topic.
    Drug Metabolism and Pharmacokinetics 11/2012; 28(1). DOI:10.2133/dmpk.DMPK-12-RV-085 · 2.57 Impact Factor
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    ABSTRACT: 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 t1/2 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 AUC0-12 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.
    International journal of clinical pharmacology and therapeutics 08/2012; 50(10):689-700. DOI:10.5414/CP201763 · 1.22 Impact Factor
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    ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is important to the antitumor effect of 5-fluorouracil (5-FU). DPD gene (DPYD) expression in tumors is correlated with sensitivity to 5-FU. Because the 5-FU accumulated in cancer cells is also rapidly converted into inactivated metabolites through catabolic pathways mediated by DPD, high DPD activity in cancer cells is an important determinant of the response to 5-FU. DPD activity is highly variable and reduced activity causes a high risk of 5-FU toxicity. Genetic variation in DPYD has been proposed as the main factor responsible for the variation in DPD activity. However, only a small proportion of the activity of DPD can be explained by DPYD mutations. In this study, we found that DPYD is a target of the following microRNAs (miRNA): miR-27a, miR-27b, miR-134, and miR-582-5p. In luciferase assays with HepG2 cells, the overexpression of these miRNAs was associated with significantly decreased reporter activity in a plasmid containing the 3'-UTR of DYPD mRNA. The level of DPD protein in MIAPaca-2 cells was also significantly decreased by the overexpression of these four miRNAs. The results suggest that miR-27a, miR-27b, miR-134, and miR-582-5p post-transcriptionally regulate DPD protein expression. The levels of miRNAs in normal lung tissue and lung tumors were compared; miR-27b and miR-134 levels were significantly lower in the tumors than normal tissue (3.64 ± 4.02 versus 9.75 ± 6.58 and 0.64 ± 0.75 versus 1.48 ± 1.39). DPD protein levels were significantly higher in the tumors. Thus, the decreased expression of miR-27b would be responsible for the high levels of DPD protein. This study is the first to show that miRNAs regulate the DPD protein, and provides new insight into 5-FU-based chemotherapy.
    Lung cancer (Amsterdam, Netherlands) 02/2012; 77(1):16-23. DOI:10.1016/j.lungcan.2011.12.018 · 3.96 Impact Factor
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    ABSTRACT: Organic cation transporters (OCTs) mediate the transport of organic cations and some drugs (e.g., metformin and cimetidine). OCT1, OCT2, and OCT3 are located in the imprinting cluster of the insulin-like growth factor 2 receptor. It has been reported that OCT1 and OCT3 show a biallelic expression, whereas OCT2 undergoes maternal imprinting in the human placenta; however, a loss of the imprinting of OCT2 has recently been reported in some placental samples. This study investigated whether epigenetic mechanisms are involved in interindividual differences in the placental expression of OCT2. Because OCT2 mRNA levels were higher in biallelic samples than that in monoallelic samples, we compared the DNA methylation and chromatin modifications in the promoter regions. There was no remarkable difference in DNA methylation between the mono allelic samples and biallelic samples. In contrast, histone H3 acetylation (H3Ac) was increased in the biallelic samples. A significant negative correlation was observed between the trimethylation of lysine-9 on histone H3 (H3K9me3) and the OCT2 mRNA levels. Our results suggest that H3Ac plays a role in the allelic expression of OCT2. In addition, H3K9me3 in the OCT2 promoter may explain the interindividual differences in placental OCT2 mRNA levels.
    Journal of Pharmaceutical Sciences 09/2011; 100(9):3875-83. DOI:10.1002/jps.22595 · 2.59 Impact Factor
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    ABSTRACT: 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.
    The Journal of Clinical Pharmacology 05/2011; 52(7):1078-89. DOI:10.1177/0091270011408612 · 2.48 Impact Factor
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    ABSTRACT: The present study was undertaken to identify genetic polymorphisms of multidrug resistance-associated protein 3 (MRP3, gene name ABCC3), an ATP-binding cassette transporter that mediates the transport of substrates across the basolateral membrane into the blood, and to investigate their effects on ABCC3 expression and MRP3 function. We identified genetic polymorphisms of ABCC3 and evaluated the effects by (1) a luciferase reporter gene assay, (2) measuring mRNA levels, and (3) a human pharmacogenomics study with 4-methylumbelliferone glucuronide (4-MUG). Overall, 61 genetic variants were 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 allele frequencies showed considerable inter-ethnic differences. The reporter gene assay indicated a significant reduction of transcriptional activity with the -1767G>A allele compared to the wild-type allele; however, a decreased expression of ABCC3 mRNA was not detected in human liver samples. A human pharmacokinetic study showed that the ABCC3 genotype in the promoter region was not associated with changes in the pharmacokinetics of 4-MUG, a substrate of MRP3. This is the first study to assess the effects of ABCC3 polymorphisms on human pharmacokinetics; however, further investigations are needed to complete the picture.
    Drug Metabolism and Pharmacokinetics 04/2011; 26(4):374-86. DOI:10.2133/dmpk.DMPK-10-RG-103 · 2.57 Impact Factor
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    ABSTRACT: Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h)=2.85×(creatinine clearance/60.9)0.618×0.472CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, ≤30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.
    Antimicrobial Agents and Chemotherapy 02/2011; 55(5):1867-73. DOI:10.1128/AAC.01185-10 · 4.48 Impact Factor
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    ABSTRACT: The Dubin-Johnson syndrome (DJS) is an inherited liver disorder characterized by conjugated hyperbilirubinemia and caused by ABCC2 gene mutations resulting in deficiency of multidrug resistance associated-protein 2 (MRP2) function. A 76-year-old woman with serious jaundice was referred to our hospital. She was clinically diagnosed with DJS with hepatic congestion, due to constrictive pericarditis. We analyzed all exons and exon-intron junctions of the ABCC2 gene by DNA sequencing and identified a new large-scale deletion, 1008 bp, including the whole exon 7, as homozygosity. Some mutations in the ABCC2 gene associated with splicing errors have been reported in intronic regions; however, this is a new type of large-scale deletion detectable in the genomic DNA sequence. Severe hyperbilirubinemia is rare in patients with constrictive pericarditis and this case suggests that MRP2 may play a crucial role in compensating for the serum bilirubin in congestive hepatopathy.
    Drug Metabolism and Pharmacokinetics 01/2009; 24(5):464-8. DOI:10.2133/dmpk.24.464 · 2.57 Impact Factor
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    ABSTRACT: The impact of SLCO1B1 polymorphism on the pharmacokinetics of olmesartan and on the pharmacokinetic interaction between pravastatin and olmesartan was investigated. On day 1, ten healthy volunteers took an oral dose (10 mg) of pravastatin. After a 3-day washout period, each subject received olmesartan medoxomil (10 mg) for 3 days. On day 8, they received olmesartan medoxomil (10 mg) and pravastatin (10 mg) concurrently, and pharmacokinetic profiles were compared with those in each single-dose phase with regard to the SLCO1B1 genotypes (*1b/*1b, *1b/*15, and *15/*15). In the single-dose phase, the mean C (max) and AUC(0-24) of olmesartan tended to be higher in *15/*15 subjects than in *1b/*1b subjects, while the mean CL( t )/F (+/-SD) in *15/*15 subjects was significantly lower than that in *1b/*1b subjects. No statistically significant differences were observed in any pharmacokinetic parameters between single-dose and co-administration phases for both pravastatin and RMS-416. These results suggest that OATP1B1 plays a role in the pharmacokinetics of olmesartan, and the co-administration of olmesartan does not affect the pharmacokinetics of pravastatin or its metabolite, RMS-416, although larger scale clinical studies are needed to confirm these observations due to the small sample size in the present study.
    Journal of Human Genetics 10/2008; 53(10):899-904. DOI:10.1007/s10038-008-0324-9 · 2.46 Impact Factor
  • Takeshi Hirota · Hiroshi Takane · Shun Higuchi · Ichiro Ieiri
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    ABSTRACT: Drug metabolizing enzymes and transporters are increasingly recognized as key determinants of the inter-individual variability in pharmacokinetic (PK) and pharmacodynamic (PD) outcomes of clinically important drugs. To date, most studies investigating this variability have focused on polymorphisms (e.g. SNPs) in the genes encoding metabolic enzymes and transporters; however, it has recently been reported that the expression of some of these genes is under the control of epigenetic mechanisms. The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolizing enzymes and transporter genes.
    Current Drug Metabolism 02/2008; 9(1):34-8. DOI:10.2174/138920008783331130 · 2.98 Impact Factor

Publication Stats

857 Citations
85.16 Total Impact Points


  • 2003–2015
    • Kyushu University
      • • Graduate School of Pharmaceutical Sciences
      • • Graduate School of Law
      Hukuoka, Fukuoka, Japan
  • 2011
    • Tottori University
      • Faculty of Medicine
      TTJ, Tottori, Japan
  • 2009
    • Saiseikai Maebashi Hospital
      Edo, Tōkyō, Japan