Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 26 , Issue 5
Showing 1-14 articles out of 14 articles from the selected issue
Editorial
Regular Article
  • Yasuhiro YAMAZAKI, Takahiro HASHIZUME, Hiroko MORIOKA, Satoshi SADAMIT ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 442-450
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: May 31, 2011
    JOURNALS FREE ACCESS
    Supplementary material
      The ATP-binding cassette half-transporters Abcg5 and Abcg8 promote the secretion of neutral sterols into bile. Studies have demonstrated the diet-induced expression of these transporters in liver, but precisely where this occurs remains to be elucidated. This study investigated the changes in the expression of these transporters in bile canaliculi in cholesterol-loaded livers. Mice were fed either a standard (SD) diet or a high-fat and high-sucrose (HF/HS) diet for 3 weeks. Bile canaliculi proteins and cryosections were prepared from the liver, and the protein levels and distribution of Abcg5/Abcg8 were determined. The high-calorie diet induced a marked accumulation of lipids in mouse liver. Protein levels of Abcg5 and Abcg8 in bile canaliculi were significantly increased by the HF/HS diet compared to the SD diet. No significant differences in Abca1, Abcb4 (Mdr2), Abcb11 (Bsep), or Abcc2 (Mrp2) levels were observed. Immunohistochemical analyses confirmed that these increases occurred in bile canaliculi. These results suggest that diet-induced lipid loading of the liver causes a significant increase in the expression of Abcg5 and Abcg8 in bile canaliculi.
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  • Norihito SHIBAHARA, Yuiko MASUNAGA, Shunsuke IWANO, Hiroshi YAMAZAKI, ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 451-457
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: June 07, 2011
    JOURNALS FREE ACCESS
      Cytochrome P450 (CYP) 1A1 is involved in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) and is induced by several compounds, including PAHs. The induction of CYP1A1 mediated by the aryl hydrocarbon receptor (AhR) has been well investigated; however, little has been reported on the mechanisms of CYP1A1 induction mediated by factors other than AhR. In this study, we investigated the involvement of liver X receptor alpha (LXRα) in the induction of CYP1A1. TO-901317, an LXRα ligand, induced CYP1A1 mRNA in a dose-dependent fashion. Luciferase reporter assays using HepG2 cells showed that TO-901317 was capable of activating the promoter of the CYP1A1 gene and that a direct repeat 4 (DR4) motif located in a region from −452 to −467 was required for the induction of CYP1A1 through LXRα. Specific binding of LXRα to this DR4 motif was confirmed by gel shift and chromatin immunoprecipitation assays. Co-treatment of HepG2 cells with TO-901317 and 2,3,7,8-tetrachlorodibenzo-p-dioxin, a typical AhR ligand, caused the synergistic induction of CYP1A1 mRNA. Thus, we propose that the expression of CYP1A1 is regulated by LXRα as well as by AhR, suggesting that exposure to both LXRα and AhR ligands can result in the alteration of individual susceptibility to environmental carcinogens metabolically activated by CYP1A1.
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  • Christian FRIEDRICH, Erika RICHTER, Dirk TROMMESHAUSER, Sandra DE KRUI ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 458-464
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: June 21, 2011
    JOURNALS FREE ACCESS
      The aim of this study was to determine whether administration of the prodrugs bisacodyl (Bisa) and sodium picosulfate (SPS) leads to excretion of their common active metabolite, bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), in breast milk. Two groups of 8 healthy lactating women who had stopped breast feeding received multiple doses of Bisa or SPS. Plasma, urine, and breast milk were collected and concentrations of free and total BHPM were determined using validated liquid chromatography/mass spectrometry methods. BHPM remained below the limits of detection in breast milk following single- and multiple-dose administration of Bisa and SPS. First, BHPM plasma concentrations were observed after a lag time of about 3 to 4 h and 4 to 5 h following Bisa and SPS administration, respectively. Cmax was attained approximately 5 h after dosing of Bisa and 9 h after dosing of SPS. BHPM did not accumulate after multiple administrations of Bisa and only slightly accumulated following multiple doses of SPS. About 12% and 13% of Bisa and SPS was excreted as BHPM into urine at steady state. BHPM, the active moiety of Bisa and SPS, was not excreted into human breast milk. Hence, use of Bisa or SPS to treat constipation of breast-feeding women is considered well tolerated with regard to exposing infants to BHPM via breast milk.
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  • Fumihiro NAKAMORI, Yoichi NARITOMI, Masako FURUTANI, Fujiko TAKAMURA, ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 465-473
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: July 05, 2011
    JOURNALS FREE ACCESS
    Supplementary material
      A method for quantitatively predicting the hepatic clearance of drugs by UDP-glucuronosyltransferases (UGTs) from in vitro data has not yet been established. We examined the relationship between in vitro and in vivo intrinsic clearance by rat hepatic UGTs using 10 drugs. For these 10 drugs, the in vitro intrinsic clearance by UGTs (CLint, in vitro) measured using alamethicin-activated rat liver microsomes was in the range 0.10–4500 ml/min/kg. Microsomal binding (fu, mic) was determined to be in the range 0.29–0.95 and the unbound intrinsic clearance (CLuint, in vitro) to be in the range 0.11–9600 ml/min/kg. The contribution of rat hepatic glucuronidation to drug elimination was 12.0%–76.6% and in vivo intrinsic clearance by UGTs was 5.7–9000 ml/min/kg. To evaluate the discrepancy between the in vitro and in vivo values, a scaling factor was calculated (CLint, in vivo/CLint, in vitro); the values were found to be in the range 0.89–110. The average fold error of the scaling factor values incorporating fu, mic was closer to unity than that without fu, mic. The scaling factor values incorporating fu, mic were <10 in 8/10 drugs and <2 in 6/10 drugs, indicating a small discrepancy between in vitro and in vivo values. Thus, using alamethicin-activated liver microsomes, incorporating fu, mic into CLint, in vitro, and considering the contribution of glucuronidation may enable us to quantitatively predict in vivo hepatic glucuronidation from in vitro data.
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  • Junya NAGAI, Koya SATO, Ryoko YUMOTO, Mikihisa TAKANO
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 474-485
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: June 28, 2011
    JOURNALS FREE ACCESS
    Supplementary material
      In this paper, we characterize the uptake mechanism of fluorescein isothiocyanate-labeled human immunoglobulin G (FITC-hIgG) in opossum kidney (OK) epithelial cells, which have been shown to express megalin and cubilin. Confocal immunofluorescence microscopy showed the punctate expression of the neonatal Fc receptor FcRn in the cytoplasm, but not on the cell surface membrane. Temperature- and energy-dependent uptake of FITC-hIgG was observed at pH 7.4 but not at pH 6.0, indicating that the internalization of FITC-hIgG might not be due to FcRn, which has a binding affinity for IgG under acidic conditions. Under physiological pH conditions, human and bovine serum γ-globulin decreased FITC-hIgG uptake in a concentration-dependent manner. In addition, FITC-hIgG uptake was inhibited by various megalin and/or cubilin ligands including albumin, cytochrome c, transferrin and gentamicin. Endosomal acidification inhibitors (bafilomycin A1 and chloroquine) significantly decreased the uptake of FITC-hIgG. Clathrin-dependent endocytosis inhibitors (phenylarsine oxide and chlorpromazine) decreased FITC-hIgG uptake. Potassium depletion and hypertonicity, conditions known to inhibit clathrin-dependent endocytosis, also decreased FITC-hIgG uptake. In contrast, caveolin-dependent endocytosis inhibitors (nystatin and methyl-β-cyclodextrin) did not decrease, but rather increased the uptake of FITC-hIgG. These observations suggest that the internalization of FITC-hIgG in OK cells might be, at least in part, due to megalin/cubilin-mediated, clathrin-dependent endocytosis.
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  • Yuichi UWAI, Yukihiro OZEKI, Tomonori ISAKA, Hiroaki HONJO, Kikuo IWAM ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 486-493
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: June 21, 2011
    JOURNALS FREE ACCESS
      Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p-aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 µM for hOAT1 and 5.4 µM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid.
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  • Qi MIAO, Qi LIU, Changyuan WANG, Qiang MENG, Xinjin GUO, Jinyong PENG, ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 494-502
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: June 28, 2011
    JOURNALS FREE ACCESS
      The aim of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 and zinc. The plasma concentration of JBP485 after oral administration in vivo, the plasma concentration of JBP485 from the portal vein after jejunal perfusions in situ, the serosal fluid concentration of JBP485 in everted small intestine preparations and the uptake of JBP485 by HeLa-hPEPT1 cells in vitro were determined by LC-MS/MS. RT-PCR and Western blotting were used to determine the mRNA and protein levels of Pept1 in the intestinal mucosa. The AUCs of JBP485 in in vivo, in vitro and in situ studies were significantly decreased after zinc pre-administration. Kinetic analysis showed that zinc inhibits the uptake of JBP485 by decreasing the affinity of JBP485 for PEPT1 in HeLa-hPEPT1 cells. RT-PCR and Western blotting indicated that zinc had no effect on basal intestinal Pept1 expression. Our results are novel in demonstrating for the first time that zinc ions, but not zinc gluconate, can inhibit the transport activity of PEPT1. In addition, the uptake of JBP485 was not affected by changes in pH values after zinc treatment. Zinc decreases the absorption of JBP485 by inhibiting the transport activity of PEPT1; however, basal intestinal Pept1 expression does not change.
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  • Makoto MIYAZAKI, Toshiki FUJII, Nobuhiro TAKEDA, Hiroaki MAGOTANI, Kaz ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 503-515
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: June 28, 2011
    JOURNALS FREE ACCESS
      The circadian relationship between the pharmacokinetics and pharmacodynamics of tolbutamide in rats was analyzed using a compartment model. The basal concentration of plasma glucose had a circadian rhythm with the acrophase at 15:19 h. After intravenous administration of tolbutamide at 06:00, 14:00, or 18:00 h, the hypoglycemic effect showed a circadian variation, with the greatest effect at 18:00 h and the lowest effect at 06:00 h. The time courses of unbound tolbutamide concentration in plasma after intravenous administration were predicted using the model-estimated total concentration of tolbutamide and the albumin concentration and resulted in profiles that did not vary with the time of administration. Significant low insulin resistance was observed at 18:00 h to i.v. glucose and insulin loads. There was no obvious time dependency in the expression of glucose transporter 4 (GLUT4) in epididymal adipocytes. The hypoglycemic rate estimated from the plasma glucose concentration was described by the conventional pharmacokinetic-pharmacodynamic model with an effect compartment. The time courses of theoretical signals in the effect compartment described the observed circadian changes in the increased expression profile of GLUT4 normalized by the increased plasma insulin (IRI) concentration (ΔGLUT4/ΔIRI) after dosing. Thus, the time dependency in glucose uptake is responsible for the circadian variation of the hypoglycemic effect of tolbutamide.
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  • Yuichiro TAMAKI, Tomio ARAI, Haruhiko SUGIMURA, Takamitsu SASAKI, Masa ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 516-522
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: July 26, 2011
    JOURNALS FREE ACCESS
      Genetic polymorphisms of enzymes involved in the metabolism of carcinogens are suggested to modify an individual's susceptibility to lung cancer. The purpose of this study was to investigate the relationship between lung cancer cases in Japan and variant alleles of cytochrome P450 (CYP) 2A6 (CYP2A6*4), CYP2A13 (CYP2A13*1-*10), CYP4B1 (CYP4B1*1-*7), sulfotransferase 1A1 (SULT1A1*2), glutathione S-transferase M1 (GSTM1 null), and glutathione S-transferase T1 (GSTT1 null). We investigated the distribution of these polymorphisms in 192 lung cancer patients and in 203 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using various techniques including allele-specific PCR, hybridization probe assay, multiplex PCR, denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. We also investigated allele and genotype frequencies and their association with lung cancer risk, demographic factors, and smoking status. The prevalence of the CYP2A6*4/*4 genotype in lung cancer cases was 3.6%, compared with 9.4% in the controls (adjusted OR = 0.36, 95% CI = 0.15–0.88, P = 0.025). In contrast, there was no association between the known CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1 polymorphisms and lung cancer. These data indicate that CYP2A6 deletions may be associated with lung cancer in the Japanese population studied.
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  • Yuka OHATA, Yoshiko TOMITA, Mitsunobu NAKAYAMA, Tsuneo KOZUKI, Keisuke ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 523-531
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: July 12, 2011
    JOURNALS FREE ACCESS
      A population pharmacokinetic (PK) model for meropenem in Japanese pediatric patients with various infectious diseases was developed based on 116 plasma concentrations from 50 pediatric patients. The population PK parameters developed in this analysis are useful for calculation of the percent time above minimum inhibitory concentration (%T>MIC) and for optimal dosing of meropenem in pediatric patients. After dosing at 20 mg/kg t.i.d. by 0.5-h infusion (approved standard dose for pediatric patients in Japan), the target value of 50%T>MIC was achieved, indicating that 20 mg/kg t.i.d. by 0.5-h infusion is effective for susceptible bacteria. In contrast, for bacteria with higher MICs such as Pseudomonas aeruginosa (MIC ≥ 2 µg/mL), the probability of target attainment of 50%T>MIC was 60.7% at a dose of 40 mg/kg t.i.d. by 0.5-h infusion (highest dose approved for pediatric patients in Japan). The simulations described in this article indicated that 40 mg/kg t.i.d. with a longer infusion duration (e.g., 4 h) is more effective against bacteria with a MIC higher than 2 µg/mL. The predicted probability of target attainment for 50%T>MIC (97.0%) was well correlated not only to the microbiological efficacy rate (97.0%) but also to the clinical efficacy rate (95.9%) in the present phase 3 study.
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  • Fumiyasu KANSAKU, Toshio KUMAI, Kuniharu SASAKI, Makito YOKOZUKA, Maki ...
    Type: Regular Article
    2011 Volume 26 Issue 5 Pages 532-537
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: August 23, 2011
    JOURNALS FREE ACCESS
      Propofol (2,6-diisopropylphenol) is administered intravenously for induction and maintenance of anesthesia; however, cases of progressive myocardial failure (propofol syndrome) related to the use of propofol have been reported. In the present study, the individual differences in pharmacokinetics and/or pharmacodynamics of propofol were investigated in patients who were genotyped for CYP2B6 and UGT1A9. Fifty-one patients treated with propofol in St. Marianna University Hospital were recruited for this study and provided written informed consent. The following parameters were analyzed: awakening time as a pharmacodynamic parameter, duration of propofol infusion, drug concentration in plasma after treatment, genotypes of CYP2B6 and UGT1A9, and age (42–84 years, mean of 65 years). Propofol was rapidly cleared from the blood of the subjects as a result of distribution and elimination. The awakening time after stopping propofol infusion was significantly correlated with the duration of infusion and the maximum concentration of propofol in these subjects. The maximum plasma concentration of propofol after normalizing with the duration of infusion was affected by the CYP2B6 G516T variant (related to impaired function) and was significantly affected by a propofol risk index score that incorporated CYP2B6 G516T and UGT1A9 I399C>T (high expression) genotypes and advanced age. These results provide important information indicating that the genotypes of the two enzymes studied and advanced age are combinative determinant factors of the pharmacokinetics and/or pharmacodynamics of propofol.
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Note
  • Miki FUKAO, Kazuya ISHIDA, Takuya SAKAMOTO, Masato TAGUCHI, Hiroyoshi ...
    Type: Note
    2011 Volume 26 Issue 5 Pages 538-543
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: July 05, 2011
    JOURNALS FREE ACCESS
      The aim of the present study was to investigate the genetic factors responsible for the interindividual variability in the bioavailability of mizoribine. Thirty healthy Japanese men aged 20–49 years and weighing 53–75 kg participated in the present study and took 150 mg of mizoribine. Urine samples were collected periodically for 12 h after the dose, and the bioavailability of mizoribine was calculated from the estimated total urinary excretion from time zero to infinity. The bioavailability of mizoribine in the 30 subjects ranged from 60.3% to 99.4%. The mean bioavailability of mizoribine in subjects with the concentrative nucleoside transporter 1 (SLC28A1) 565-A/A allele (75.4%) was significantly lower than that in subjects with the SLC28A1 565-G/G allele (90.1%). On the other hand, the bioavailability of mizoribine was not affected by polymorphisms of breast cancer resistance protein (ABCG2) C421A and multidrug resistance-associated protein 4 (ABCC4) G2269A. The findings in the present prospective study suggested that the genetic test for the SLC28A1 G565A polymorphism is promising for predicting the Japanese subjects with lower bioavailability of mizoribine.
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SNP Communication
  • Yuichiro TAMAKI, Masashi HONDA, Yuka MUROI, Tomio ARAI, Haruhiko SUGIM ...
    Type: SNP Communication
    2011 Volume 26 Issue 5 Pages 544-547
    Published: 2011
    Released: October 28, 2011
    [Advance publication] Released: May 24, 2011
    JOURNALS FREE ACCESS
      Cytochrome P450 2A13 (CYP2A13) is a human CYP enzyme that is selectively expressed in the respiratory tract. It plays an active role in the metabolic activation of a tobacco-specific procarcinogen. In this study, the entire coding sequence and the exon-intron junctions of the CYP2A13 gene obtained from 395 Japanese individuals were screened for genetic polymorphisms. Eight genetic polymorphisms were found, of which seven gave rise to known variant alleles: CYP2A13*2, CYP2A13*3, CYP2A13*4, CYP2A13*6, and CYP2A13*7. We identified a novel single nucleotide polymorphism (SNP), 5792T>C, in exon 7 that caused an amino acid substitution (Ile331Thr). One of the 395 individuals included in the study was heterozygous for the variant allele, and therefore, the frequency of the allele in the study population was 0.13%.
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