Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 22 , Issue 1
Showing 1-9 articles out of 9 articles from the selected issue
Editorial
Review
  • Shigehiro OHDO
    2007 Volume 22 Issue 1 Pages 3-14
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      The mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm. Clock genes are the genes that control the circadian rhythms in physiology and behavior. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24 hr rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Such chronopharmacological phenomena are influenced by not only the pharmacokinetics but also pharmacodynamics of medications. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The mechanisms underlying chronopharmacological findings should be clarified from the viewpoint of clock genes. On the other hand, several drugs have an effect on circadian clock. The knowledge of interactions between circadian clock and drugs should be very useful for clinical practice. Therefore, I introduce the regulatory system of biological rhythm from viewpoints of clock genes and the possibility of pharmacotherapy based on clock genes.
    Download PDF (236K)
Regular Articles
  • Yukiko MINAMIYAMA, Shigekazu TAKEMURA, Susumu IMAOKA, Yoshihiko FUNAE, ...
    2007 Volume 22 Issue 1 Pages 15-19
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      Nitric oxide (NO) biotransformation from NO-aspirin (NCX-4016) is not clearly understood. We have previously reported that cytochrome P450 (P450) plays important role in NO generation from other organic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate (ISDN). The present study was designed to elucidate the role of human cytochrome P450 isoforms in NO formation from NCX-4016, using lymphoblast microsomes transfected with cDNA of human P450 or yeast-expressed, purified P450 isoforms. CYP1A2 and CYP2J2, among other isoforms, were strongly related to NO production from NCX-4016. In fact, these isoforms were detected in human coronary endothelial cells. These results suggest that NADPH-cytochrome P450 reductase and the P450 system participate in NO formation from NCX-4016, as well as other organic nitrates.
    Download PDF (837K)
  • Yoko FURUYA, Takeshi OZEKI, Risa TAKAYANAGI, Haruko YOKOYAMA, Kiyoshi ...
    2007 Volume 22 Issue 1 Pages 20-25
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      Tumor necrosis factor (TNF)-α, a primary mediator of inflammatory responses, is increased in patients with active Crohn's disease (CD) and considered to play an important role in the regulation of inflammation in CD. Infliximab (IFX) is a chimeric murine-human monoclonal IgG1 antibody that targets TNF-α and is used as a therapeutic agent for CD. Although that dosage regimen has been established through clinical trial experience, it has not been analyzed theoretically. We analyzed of sequential changes of the Crohn's disease activity index (CDAI) using a pharmacokinetic-pharmacodynamic model integrating the pharmacokinetics of IFX and turnover rate of TNF-α. The time course effects of IFX derived from the present model were matched to reported data regarding CDAI ratios, and we found that the clinical effect of IFX reached a maximum value 2 to 4 weeks after administration and was maintained for the next several weeks. Our results suggested that the standard dosage regimen of IFX is theoretically appropriate. Further, based on the results of various dosage regimens, a second administration of IFX 2 weeks after the first dose was shown to achieve remission in the early stage of active CD, when IFX was given as a repeated treatment.
    Download PDF (155K)
  • Yoshimine FUJII, Masayuki TAKAHASHI, Hiromi MORITA, Hiroshi KIKUCHI, Y ...
    2007 Volume 22 Issue 1 Pages 26-32
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      DX-9065a, a newly synthesized anticoagulant that selectively inhibits factor Xa, is a zwitterion and has characteristics of high water solubility and low lipophilicity. We predicted the fraction absorbed (Fa) of DX-9065a to be approximately 15-35% in humans, based on the boundary layer theory using the intestinal perfusion method in rats. However, human oral bioavailability was 2-3% in clinical trials, and the result of actual human bioavailability was lower than that of the predicted Fa. Thus, in this report, the reason for low oral bioavailability of DX-9065a was examined by in vitro and in vivo experiments. The factors affecting oral bioavailability of DX-9065a were not the hepatic first-pass effect, degradation of the drug in intestinal fluid, nor the interaction of the drug with the intestinal mucin. Furthermore, no effect of P-gp efflux was observed. Oral absorption of the drug in rats with bile duct ligation was significantly higher than that in normal rats with bioavailability of 17 and 3%, respectively. It was confirmed that bile acids inhibited DX-9065a absorption because DX-9065a interacted with bile acids to form insoluble complexes. The results suggest that the complex formation of DX-9065a with bile acids in the intestinal tract is an important factor affecting absorption of DX-9065a.
    Download PDF (238K)
  • Tomoya NARAWA, Yasuyuki TSUDA, Tomoo ITOH
    2007 Volume 22 Issue 1 Pages 33-40
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      Stereoselectivity of the human reduced folate carrier (RFC1) in Caco-2 cells was examined using methotrexate (L-amethopterin, L-MTX) and its antipode (D-amethopterin, D-MTX) as model substrates. The initial uptake rate of L-MTX into Caco-2 cells followed Michaelis-Menten kinetics with a Km value of approximately 1 μM. The Eadie-Hofstee plot of the RFC1-mediated L-MTX uptake showed that it was mediated by a single transport system, RFC1. Dixon plots revealed that L-MTX uptake was inhibited competitively by folic acid (FA), L-MTX and D-MTX, with Ki values of approximately 0.8, 1.5 and 180 μM, respectively. The results showed that the affinities of FA and L-MTX to RFC1 were approximately 120-fold greater than that of D-MTX. The uptake of L- and D-MTX into Caco-2 cells was also measured using LC-MS/MS analysis, which revealed that the L-MTX uptake was at least 7-fold greater than that of D-MTX. The present study revealed significant stereoselectivity of RFC1 toward amethopterin enantiomers with the L-isomer being much more favored.
    Download PDF (187K)
  • Takahiro SHIBAYAMA, Daisuke SUGIYAMA, Emi KAMIYAMA, Taro TOKUI, Takash ...
    2007 Volume 22 Issue 1 Pages 41-47
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      To characterize the renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, and meropenem in humans, we examined their affinities as substrates to human renal transporters. In vitro studies on the uptake of [14C]CS-023 and [14C]meropenem were conducted using HEK293 cells expressing human organic anion transporters (hOAT) 1, hOAT3, hOAT4, and the human organic cation transporters (hOCT) 1 and hOCT2. CS-023 did not serve as the substrate for any of the transporters tested. On the other hand, meropenem was transported by hOAT1 and hOAT3. The Km value of the hOAT3-mediated transport was 847 μM, and the uptake was inhibited by probenecid, p-aminohippurate and benzylpenicillin with Ki values of 3.76, 712, and 202 μM, respectively. One of the reasons why CS-023 is not a substrate of hOATs, and vice versa for meropenem, would be that a very small proportion of CS-023 exists as the anionic form at the physiological pH, whereas 50% of meropenem exists as the anionic form. These findings indicate that the lack of recognition of CS-023 by renal transporters is one of the reasons for its long plasma half-life in humans compared with meropenem which undergoes renal tubular secretion mediated by hOAT1 and hOAT3.
    Download PDF (221K)
SNP Communications
  • Hiromi FUKUSHIMA-UESAKA, Yoshiro SAITO, Masahiro TOHKIN, Keiko MAEKAWA ...
    2007 Volume 22 Issue 1 Pages 48-60
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5′-flanking region, 1 in the 5′-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3′-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5′-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on ≥10 chromosomes accounted for ≥91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.
    Download PDF (6169K)
  • Makiko SHIMIZU, Sachiko TOMIOKA, Norie MURAYAMA, Hiroshi YAMAZAKI
    2007 Volume 22 Issue 1 Pages 61-64
    Published: 2007
    Released: March 01, 2007
    JOURNALS FREE ACCESS
      We sequenced all exons and exon-intron junctions of the flavin-containing monooxygenase 3 (FMO3) gene from 3 Japanese individuals and their family members, who were case subjects that showed low FMO3 metabolic capacity among a population of self-reported trimethylaminuria Japanese volunteers (n=50). We found three novel single nucleotide polymorphisms (SNPs) (g. 20752 A>G, g. 27400 G>A, and g. 30308 C>T) causing an amino acid substitution and stop codons, Asn114Ser in exon 4, Trp388Stop in exon 7, and Gln470Stop in exon 9, respectively. The Trp388Stop and Gln470Stop also presented together with known SNPs, Val257Met and Glu158Lys, respectively, in the same alleles of the FMO3 gene to form novel haplotypes.
       These sequences are as follows:
      1) SNP, 060825Shimizu004; GENE NAME, FMO3; ACCESSION NUMBER, AL021026; LENGTH, 25 base; 5′-TATCCAGTGTAAA/GTAAACATCCTGA-3′.
      2) SNP, 060825Shimizu005; GENE NAME, FMO3; ACCESSION NUMBER, AL021026; LENGTH, 25 base; 5′-CCAGTCCCGCTGG/AGCAGCACAAGTA-3′.
      3) SNP, 060825Shimizu006; GENE NAME, FMO3; ACCESSION NUMBER, AL021026; LENGTH, 25 base; 5′-TGTAGTCCCTACC/TAGTTTAGGCTGG-3′.
    Download PDF (651K)
feedback
Top