Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 26 , Issue 3
Showing 1-12 articles out of 12 articles from the selected issue
Editorial
Review
  • Yoshihisa SHITARA
    Type: Review
    2011 Volume 26 Issue 3 Pages 220-227
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: February 01, 2011
    JOURNALS FREE ACCESS
      OATP1B1 and OATP1B3 are transporters that are expressed on the sinusoidal membrane of hepatocytes; they accept a number of therapeutic reagents as their substrates. In vitro and in vivo studies have shown that some drugs inhibit these transporters and cause clinically relevant drug–drug interactions (DDIs). Among these drugs, cyclosporin A markedly increases the plasma concentrations of OATP1B1 substrates. In such cases, the area under the plasma concentration–time curve and the maximum concentration of the affected drugs are increased to a similar degree. Even for OATP1B1 substrates that are metabolized in the liver, the hepatic uptake rate is a determinant of overall hepatic clearance, and the DDIs are partly caused by the inhibition of OATP1B1. Gemfibrozil displays DDIs with some OATP1B1 substrates, although their extent is small. Rifampicin and some HIV protease inhibitors are also OATP1B1 inhibitors. Rifampicin is also an inducer of metabolic enzymes, and although its single coadministration produces an increase in the plasma concentration of the affected drugs, multiple coadministrations may result in reductions in the plasma concentrations of OATP1B1 and CYP3A4 bisubstrates. As a large number of therapeutic reagents are substrates and/or inhibitors of OATP1B1 and OATP1B3, we should be aware of DDIs caused by the inhibition of these transporters.
    Download PDF (163K)
Regular Article
  • Ryota ISE, Shotaro UEHARA, Hideo AKIYAMA, Satoshi KONDO, Kazuhide IWAS ...
    Type: Regular Article
    2011 Volume 26 Issue 3 Pages 228-235
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: January 25, 2011
    JOURNALS FREE ACCESS
      Cytochromes P450 (P450s or CYPs) are a gene family of highly homologous genes and include the CYP1–4 family, which is relevant to drug metabolism. In the cynomolgus monkey (which is frequently used in drug metabolism studies), numerous CYPs (mfCYPs) have been identified in the CYP1–4 family. DNA microarrays are useful for high-throughput screening assays; however, there is a potential problem with cross-hybridization of highly homologous genes in the gene family. This problem might be solved with the use of low-density DNA microarrays, with which specific validation can be performed for the genes on the microarray. We have developed a DNA microarray for the 20 mfCYPs and have evaluated and validated its specificity and usefulness. First, in both DNA microarray and quantitative polymerase chain reaction (qPCR) analyses, hepatic expression of each mfCYP correlated well, and similar tissue expression patterns were observed for five representative mfCYPs, confirming the specificity of the DNA microarray. Second, the usefulness of this DNA microarray was validated by induction analysis of mfCYPs in primary hepatocytes, which successfully detected known responders, but also novel responders (mfCYP2C43, mfCYP2C75, and mfCYP3A5 for rifampicin), as confirmed by qPCR analysis. This DNA microarray can thus be utilized for high-throughput assays during drug development.
    Download PDF (326K)
  • Masayo OISHI, Koji CHIBA, Bimal MALHOTRA, Toshio SUWA
    Type: Regular Article
    2011 Volume 26 Issue 3 Pages 236-241
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: January 25, 2011
    JOURNALS FREE ACCESS
      Tolterodine is known as a drug which exhibits ethnic differences in pharmacokinetics between Japanese and Koreans despite genetic similarities among the populations of East Asian countries. Tolterodine is mainly metabolized by CYP2D6 to a 5-hydroxymethyl metabolite (5-HM), and 5-HM is also metabolized by CYP2D6. The reduced-function allele CYP2D6*10 is frequently observed in Asian populations. We investigated differences in the pharmacokinetics of tolterodine between small Japanese and Korean study populations by physiological and stochastic approaches with consideration of the CYP2D6 genotype. The genotype frequencies of CYP2D6*10/*10 and CYP2D6*5/*10 were found to be higher in Koreans than in Japanese, which suggested that this frequency difference occurred incidentally. The effects of CYP2D6 genotype and ethnicity on the intrinsic clearance of tolterodine by CYP2D6 were tested and only genotype was found to be a significant factor by ANCOVA. A simulation was conducted to confirm whether the observed differences in tolterodine exposure could be explained by the differences in genotype frequency found in this study. It was confirmed that the variability of intrinsic clearance could be responsible for the incidental exposure differences. In conclusion, apparent differences in exposure were found between small Japanese and Korean study populations because of the variability of intrinsic clearances and genotype frequencies.
    Download PDF (425K)
  • Yutaka TAKAHASHI, Yasuyoshi ISHIWATA, Yuko KOJIMA, Masato YASUHARA
    Type: Regular Article
    2011 Volume 26 Issue 3 Pages 242-247
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: January 25, 2011
    JOURNALS FREE ACCESS
      Hypoglycemia is one of the serious adverse effects induced by cibenzoline (CBZ), an antiarrhythmic agent. In order to clarify the pharmacodynamics of CBZ-induced hypoglycemia, CBZ was administered intravenously to conscious rats at a dose of 5, 10 or 20 mg/kg and serum samples were collected periodically to determine the concentrations of CBZ, insulin and glucose. The pharmacokinetics of CBZ showed nonlinear characteristics and could be described by a two-compartment model with Michaelis-Menten elimination kinetics. CBZ induced a rapid increase in the serum concentration of insulin. As the CBZ dose was increased, a greater hypoglycemic effect occurred. The indirect response model was applied to account for the CBZ-induced increase in insulin secretion and the subsequent decrease in serum glucose. A linear relationship was assumed between the serum concentration of CBZ and its stimulating effect on insulin secretion. A nonlinear relationship was assumed between the serum concentration of insulin and its stimulating effect on the elimination of serum glucose. The time courses of serum concentrations of CBZ, insulin and glucose after intravenous injection of CBZ could be described by the pharmacokinetic and pharmacodynamic model developed. This approach will be useful for the identification of variable factors related to CBZ-induced hypoglycemia.
    Download PDF (147K)
  • Tomotaka SHINGAKI, Ismael J. HIDALGO, Tomoyuki FURUBAYASHI, Toshiyasu ...
    Type: Regular Article
    2011 Volume 26 Issue 3 Pages 248-255
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: February 08, 2011
    JOURNALS FREE ACCESS
      The objective of this study was to evaluate in rats the potential utility of the nasal route to enhance central nervous system (CNS) delivery of drugs recognized by P-glycoprotein (P-gp). Well-known P-gp substrates verapamil and talinolol were perfused nasally or infused intravenously, and when plasma concentrations following intravenous infusion and nasal perfusion showed similar profiles. The concentration of verapamil in the brain after nasal perfusion was twice that after intravenous infusion. Although talinolol in the brain and the cerebrospinal fluid after i.v. infusion were below the detection limit, it was detected after nasal perfusion. When rats were treated with cyclosporin A, brain concentrations of verapamil after both administration modes were increased significantly, while those of talinolol were not significantly changed. Since the permeability of talinolol is low, talinolol in the brain which was transported directly from the nasal cavity has little chance of transport by P-gp localized in the apical membrane of cerebral microvessel endothelial cells. The potential for drug delivery utilizing the nose–CNS route was confirmed for P-gp substrates. The advantage of nasal delivery over i.v. delivery of talinolol to the brain was more significant than that of verapamil, suggesting that nasal administration is more useful strategy for the brain delivery of low-permeability P-gp substrates than the use of P-gp inhibitors.
    Download PDF (488K)
  • Yuko ABE, Ryoichi FUJIWARA, Shingo ODA, Tsuyoshi YOKOI, Miki NAKAJIMA
    Type: Regular Article
    2011 Volume 26 Issue 3 Pages 256-265
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: February 08, 2011
    JOURNALS FREE ACCESS
      UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of a wide variety of xeno/endobiotics. Previous studies have reported that human UGT enzymes are phosphorylated and that treatment of cells with protein kinase C (PKC) inhibitors results in decreased UGT activities without affecting the UGT protein levels. In this study, we investigated the effects of PKC inhibitors on human UGT1A protein levels and activities in detail. When UGT1A-expressing HEK293 cells and LS180 cells were treated with curcumin or calphostin C, the exogenous and endogenous UGT1A protein levels in homogenates prepared with Tris-buffered saline were significantly decreased. Enzyme activity levels mirrored the changes in UGT protein levels. When the curcumin- or calphostin C-treated cells were lysed with buffer containing a detergent, the UGT protein levels did not decrease. We found that curcumin or calphostin C treatment facilitated the degradation of UGT protein after the cells were collected in the absence of a detergent. Finally, by in cellulo evaluation, we found that curcumin decreased UGT activity by the direct inhibitory effect, but calphostin C did not affect UGT activity. Thus, this study suggests that we should evaluate the data carefully when interpreting the effects of PKC inhibitors on UGT activity.
    Download PDF (764K)
  • Sabrina X. ZHAO, Wendy WeiWei WANG, Gregory S. WALKER, Liming ZHANG, R ...
    Type: Regular Article
    2011 Volume 26 Issue 3 Pages 266-279
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: March 04, 2011
    JOURNALS FREE ACCESS
      The metabolism of 3,4-dihydro-7-[4-(1-naphthalenyl)-1-piperazinyl]butoxy]-1,8-naphthyridin-2(1H)-one (NPBN) was investigated in rats. Animals were administered 30 mg/kg NPBN that was labeled with both tritium and carbon-14. The mass recovery of drug-related material was 96–98%, with almost all material excreted in feces. Metabolism occurred by oxidation reactions followed by conjugation. The main route of metabolism of NPBN occurred via oxidation of the naphthylene ring, which led to naphthol and dihydrodiol metabolites as well as a relatively novel N-dearylated metabolite in which the naphthylene ring was removed. In vitro investigation in rat liver microsomes also showed a glutathione adduct on the naphthalene and a glutathione adduct of naphthoquinone, which, along with the dihydrodiol metabolite, is consistent with the initial generation of an epoxide. A mechanism is proposed whereby the N-dearylation arises via epoxidation, followed by formation of an exocyclic iminium ion intermediate that is hydrolyzed to yield the N-dearylated metabolite. An additional mechanism involves oxidation of the naphthol metabolite via a radical mechanism, since this metabolite was also shown to undergo N-dearylation.
    Download PDF (1947K)
  • Masato TAGUCHI, Fukiko ICHIDA, Keiichi HIRONO, Toshio MIYAWAKI, Naoki ...
    Type: Regular Article
    2011 Volume 26 Issue 3 Pages 280-287
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: March 04, 2011
    JOURNALS FREE ACCESS
      We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 − 0.0377 · (AGE − 3.81)) · WT L/h and 0.175 h−1, respectively.
    Download PDF (442K)
Note
  • Yasuharu NAKANISHI, Akinori MATSUSHITA, Kiyomi MATSUNO, Kazuhide IWASA ...
    Type: Note
    2011 Volume 26 Issue 3 Pages 288-294
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: January 25, 2011
    JOURNALS FREE ACCESS
      The cynomolgus monkey is an animal species widely used to study drug metabolism because of its evolutionary closeness to humans. However, drug-metabolizing enzyme activities have not been compared in various parts of the liver and small intestine in cynomolgus monkeys. In this study, therefore, drug-metabolizing enzyme activities were analyzed in the liver (the five lobes) and small intestine (six sections from the duodenum to the distal ileum). 7-Ethoxyresorufin O-deethylation, coumarin 7-hydroxylation, paclitaxel 6α-hydroxylation, diclofenac 4′-hydroxylation, tolbutamide methylhydroxylation, S-mephenytoin 4′-hydroxylation, bufuralol 1′-hydroxylation, chlorzoxazone 6-hydroxylation, midazolam 1′-hydroxylation, and testosterone 6β-, 16α-, 16β-, and 2α-hydroxylation were used as the probe reactions for this investigation. In liver, all probe reactions were detected and enzyme activity levels were similar in all lobes, whereas, in the small intestine, all enzyme activities were detected (except for coumarin 7-hydroxylase and testosterone 16α-hydroxylase activity), but from jejunum to ileum there was a decrease in the level of enzyme activity. This includes midazolam 1′-hydroxylation and testosterone 6β-hydroxylation, which are catalyzed by cynomolgus monkey cytochrome P450 (CYP) 3A4/5, orthologs of human CYP3A4/5, which are important drug-metabolizing enzymes. The data presented in this study are expected to facilitate the use of cynomolgus monkeys in drug metabolism studies.
    Download PDF (211K)
  • Yuya KATO, Fukiko ICHIDA, Kazuyoshi SAITO, Kazuhiro WATANABE, Keiichi ...
    Type: Note
    2011 Volume 26 Issue 3 Pages 295-299
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: January 25, 2011
    JOURNALS FREE ACCESS
      The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42–19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time–international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.
    Download PDF (297K)
Short Communication
  • Haruka NISHIMUTA, Kimihiko SATO, Yasuyuki MIZUKI, Masashi YABUKI, Sets ...
    Type: Short Communication
    2011 Volume 26 Issue 3 Pages 300-306
    Published: 2011
    Released: June 30, 2011
    [Advance publication] Released: March 04, 2011
    JOURNALS FREE ACCESS
      The oral bioavailability of some drugs is markedly lower in cynomolgus monkeys than in humans. One of the reasons for the low bioavailability in cynomolgus monkeys may be the higher metabolic activity of intestinal CYP3A; however, the species differences in intestinal metabolic activities of other CYP isoforms between cynomolgus monkeys and humans are not well known. In the present study, we investigated the intrinsic clearance (CLint) values in pooled intestinal microsomes from cynomolgus monkeys and humans using 25 substrates of human CYP1A2, CYP2J2, CYP2C, and CYP2D6. As in humans, intestinal CLint values of human CYP1A2 and CYP2D6 substrates in cynomolgus monkeys were low. On the other hand, intestinal CLint values of human CYP2J2 and CYP2C substrates in cynomolgus monkeys were greatly higher than those in humans. Using immunoinhibitory antibodies and chemical inhibitors, we showed that the higher intestinal CLint values of the human CYP2J2 and CYP2C substrates in cynomolgus monkeys might be caused by monkey CYP4F and CYP2C subfamily members, respectively. In conclusion, there is a possibility that the greatly higher metabolic activity of CYP2C and CYP4F in cynomolgus monkey intestine is one of the causes of the species difference of intestinal first-pass metabolism between cynomolgus monkeys and humans.
    Download PDF (456K)
feedback
Top