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Microsoft powerpoint - 20090826 cover students' report [互換モード]

Quantitative evaluation of drug transport and
metabolism in the body
Research Department of Genetic, Evolution and Environment, University College London (UCL), London, United Kingdom Professor Yuichi Sugiyama
Associate Professor Hiroyuki Kusuhara
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical
Sciences, The University of Tokyo
Abstract
Metformin is one of the most commonly used drugs in the United States, mainly used in the treatment of type 2 diabetes mellitus. Its most severe adverse reaction, lactic acidosis, is caused by elevated metformin plasma levels. Inhibition of MATE1, a new transporter mediating the efflux of metformin, by other drugs can lead to such elevated metformin plasma and liver levels and is therefore a potential site for drug drug interaction. This project aims to identify candidate inhibitors for MATE1 using an in vitro uptake study and LC/MS analysis as well as pharmacokinetic models to estimate the incidence of drug drug interactions in humans. So far, 7 compounds have been identified that significantly decrease metformin clearance and evaluation of the clinical relevance of these findings is currently underway. Background
Metformin, a biguanide, is one of the most commonly prescribed first-line drugs in the US1. Its main use is in the treatment of type 2 diabetes mellitus, in particular in overweight and obese patients. Advantages of metformin compared to other anti-diabetic drugs include that it does not cause hypoglycemia if used as monotherapy. Other positive effects have also been observed with regard to insulin resistance, obesity and hyperlipidemia2. Compared to its predecessors, metformin has a very good safety record and serious adverse effects are rare. However, lactic acidosis – the most severe side effect associated with metformin – can arise due to elevated metformin plasma levels (generally >5µg/ml). This primarily occurs in patients with significant renal insufficiency but the risk can also be increased by other factors, such as drug drug interaction. For example, it has long been established that cationic drugs, such as cimetidine, can increase metformin concentrations by competitive inhibition of renal tubular secretion via the organic cation transport system3. Recently, a new organic cation (OC) transporter of the Multi-drug And Toxin Extrusion family (MATE) mediating the final step in the in the excretion of toxic OCs has been identified in humans4. hMATE1 is primarily expressed in the liver and kidney, whilst hMATE2 is only expressed in the kidney. In vitro studies have already suggested that metformin is a substrate of hMATE15 and a recent in vivo study in mice has demonstrated that mMate1 is indeed vital for the systemic clearance of metformin6. This supports the hypothesis that inhibition of MATE1 can potentially lead to lactic acidosis in patients receiving metformin therapy due to the resulting increased metformin plasma levels. It is therefore important to identify potential inhibitors for MATE1 in order to prevent adverse drug reactions in diabetic patients on metformin therapy. Aim of project
The aim of this project is to identify potential candidate drugs for inhibition of MATE1 by testing the inhibition potency of the candidate drug on the clearance of metformin and evaluate the clinical relevance by using pharmacokinetic models to estimate the incidence of DDIs in patients. Selection of candidate drugs
Firstly, 1140 drugs that are reported to interact with metformin and their active compounds were identified. Out of these a final 14 candidates were selected based on reports on their effect on increased metformin plasma Cell culture and uptake study
Two cell lines were used in this project: HEK-293 stably expressing hMATE1 cells and HEK- 293 mock cells as a control. Cells were cultured in standard conditions and the uptake study followed the standar d lab protocol. Unlabeled metformin was quantified by using LC/MS. The cellular uptake of metformin was divided by medium concentrations and time to yield clearance. All cell solutions with the different compound combinations were also tested for their protein concentrations using light absorbance Data analysis
The clearance of metformin was calculated in the presence and absence of each compound. One-way ANOVA followed by Dunnett’s test were performed to determine whether a compound displayed significant inhibition potency. Unbound plasma concentrations for each compound were calculated based on published data of protein Preliminary results
Out of 14 test compounds 7 showed a significant reduction of metformin clearance compared to the control (p<0.05). In particular Amiloride, Guanethidine, Quinidine and Trimethroprim showed the largest decrease in metformin clearance. Evaluation of the clinical relevance based on unbound plasma concentrations at therapeutic dose is currently underway and will be completed soon. Depending on the result of this evaluation, further tests will be conducted to establish a Ki value using different concentrations of each compound and the results validated using canalicular membrane vesicles from human or mouse liver samples. [1] 2008 Top 200 generic drugs by total prescriptions. Drug Topics http://drugtopics.modernmedicine.com/ [2] Sweileh, W M. (2007) Contraindications to metformin therapy among patients with type 2 diabetes mellitus. Pharmacy World & Science: PWS 2007; 29(6): 587-92. [3] A Somogyi, C Stockley, J Keal, P Rolan, and F Bochner.(1987) Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987 May; 23(5): 545–551. [4] Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y (2005) A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A. 2005 Dec [5] Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K.(2007) Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 [6] Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, Inui K. (2009) Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol. 2009 This section will give a brief summary of the training I have received during the CMSI programme. Cell culture (including maintenance, passage and seeding) Assessment of protein concentration of a given solution using light absorbance measurement Data analysis (calculations based on raw data, statistical analysis, interpretation of results, follow up Principles of pharmacokinetics in order to predict potential drug drug interaction Preparation of canalicular membrane vesicles using rat liver samples I have used the first half of the programme learning and practicing these experiments and becoming acquainted with the data mining process for this particular area of research. I have then spent the second half of my stay performing the study described in the previous section. First of all, I found the lab meetings held in the style of individual presentations from each student and staff member very stimulating. It allowed everyone to stay aware of the research conducted in the group as a whole and gave everyone the opportunity to give and receive feedback from staff and students. It really helps keeping the research work focused and structured, in particular in terms of future research plans. Secondly, I have found the style of teaching/mentoring by the staff members very admirable. I was very impressed by the combination of careful guidance yet at the same time allowing the students to play an active role in determining the course of their research. It seemed to me an excellent way of gently guiding students from being “students” to becoming independently thinking “scientists” by providing more support in the beginning and then slowly increasing the responsibilities each student has over time. Thirdly, and perhaps most importantly, I have learnt much about how to improve my own working ethos by observing how people conduct their research here. I have found the working morale and atmosphere in this laboratory truly admirable. Everybody is very team work oriented, which makes it possible for many people to work together smoothly in a limited working space. Communication amongst students and staff was excellent and I think that this, together with the seminars, really helps improve the quality of the research conducted. During my stay in this laboratory I have wholeheartedly adopted this attitude and I hope that I will be able to bring it back to my home university to do my part in improving the research environment in my laboratory. As a closing comment of this report, I would like to thank the CMSI staff for organising such a wonderful progra mme, giving me the opportunity to come to Japan and conduct research here. It has been an absolutely wonderful experience for me and I have learnt a lot in the last couple of months. Not only have I acquired practical skills i n a research area completely novel for me, but I have also gained invaluable experience with regards to the Japan ese research environment. The attitude towards work and in particular the truly outstanding degree of team work displayed by people in this university have left a great impression on me and I hope that we can adapt this kind o
  • The effect of cholesterol end group to polyion complex (PIC) structure formation
  • Department of Materials Engineering
  • Polymer vesicles enclosing a volume with a molecularly thin membrane (Polymersome) has been attracting great interest from both theoretical and applications prospective. This is especially true in the field of drug delivery systems. Conventional polym.
  • Fig 1: Schematic diagram of a Nano-PICsome
  • Recently, a new semi-permeable encapsulation system namely PICsome (Fig 1), created from self-assembly of oppositely charged block copolymers in an aqueous medium have been developed. PICsome formation can be prepared under ambient conditions and allo.
  • Fig 2: The dynamic behavior of PICsome prepared from PEG-P(Asp) (45-75) and Homo-P(Asp-AP) (82)
  • This structural instability is of great concern particularly in the field of Drug delivery system. On top of this, the advantage macromolecular carriers has over other carriers is their preferential accumulation in solid tumors. Such an elevated tumor.
  • From preliminary results, cholesterol-modified block copolymer can suppress the dynamic growth of nano-PICsomes. This could be due to high hydrophobicity of cholesterol group leading to a high hydrophobic intermolecular interaction at the inner shell .
  • My research topic during my time as a CMSI summer student is on the effect of cholesterol to nano-PICsomes structure and dynamic growth. The following will be the outline of my work.
  • 1) Synthesis, purification and characterization of PEG-P(Asp)-Chol.
  • 2) Preparation of Complex (Fig.3) with different mixing ratios of cation and anion. The PICsomes will be formed from complexation of PEG-P(Asp)-Chol (Anion) and Homo-P(Asp-AP) (cation).
  • Visiting the Tokyo Women's hospital
  • Internship Affiliation and supervisor detail
  • Bio-Medical Precision Engineering (BMPE) Lab
  • Internship Affiliation and supervisor detail
  • Graduate School of Engineering, Pharmaceutical Sciences
  • Visiting the Tokyo Women's hospital
  • Source: http://park.itc.u-tokyo.ac.jp/CMSI/e/exchange/doc/2009summer/Kogleck.pdf

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