Applied Drug Metabolism

Course content

The course consists of a series of lectures combined with five sessions of laboratory exercises intended to give students a practical feeling for working with drug metabolism. As part of the assessment, students must prepare a report dealing with the metabolism of a given drug. The written report is also a learning tool, as the idea is for students to gather information continuously to respond to the questions asked during lectures and in dialogue with teachers.The following topics will be reviewed in the course of the lecture series:

  • Introduction to CYPs, their function and nomenclature, polymorfisms, prevalence and examples of clinical relevance
  • Oxidative cycle for CYP-hem complex
  • Structure/activity relationship for CYPs, starting with protein structure
  • Introduction to phase II enzymes, function and nomenclature, polymorfisms, prevalence and examples of clinical relevance
  • A short review of the authorities’ requirements to metabolism studies of new drugs and copy products
  • Overview and short review of the different in vitro methods used. Production, advantages and disadvantages. Choice of animal models for metabolism and toxicology studies – species, advantages and disadvantages. Short review of radiochemical methods. Marking, strategies and possibly calculations
  • LC-MS analytical chemical strategies and issues. Calculations and examples.
  • Studies and strategies for studying the metabolism of lead compounds in the discovery phase; timelines and overview
  • Studies and strategies for studying the metabolism of NCE in the development phase; timelines and overview
  • Issues in connection with metabolism studies of large molecules (proteins and similar)
  • Models for calculating intrinsic clearance from in vitro models. Scaling to in vivo PK and interspecies scaling
  • The function and relevance of transporters for metabolism and toxicology
  • Induction of CYPs and transporters of drugs, induction and nuclear receptors, diet etc.
  • Inhibition of metabolic enzymes and DDI
  • Significance and examples of metabolites for pharmacological/ toxicological activity
  • Examples of the utilization of pre-clinical metabolism data for planning clinical studies
  • Review of the concept chemically reactive metabolites, review of current knowledge in this area and examples of RDM
  • Introduction to the issues of forensic chemistry and how knowledge about metabolism can be utilized.

In addition to the topics mentioned above, which will be reviewed during lectures, time will be allotted for review and for questions to the written project, and to reports from laboratory exercises. It is expected that students attending these project/questions periods will actively participate in discussions in plenary and that they may possibly present some of their project or reports. There will also be five four-hour laboratory exercises consisting of ’dry’ computer exercises as well as ’wet’ laboratory exercises. The exercises provide the opportunity of combining practical and theoretical work on drug metabolism, in that we will first work with prediction and subsequently carry out in vitro tests with associated LC-MS analysis of a given drug. We will also interpret the data we obtain, and use this data for in silico study of ADME properties. The whole series of studies will result in a short written report (max. two pages) from students.

Education

MSc in Pharmaceutical Sciences - elective, MSc in Medicinal Chemistry - elective, Cand.Scient.Pharm. - elective, Cand.Pharm. - elective

MSc Programme in Environmental Science - restricted elective

Learning outcome

To give students insight into how drugs are metabolized in the body. The possible metabolic paths of drugs and the enzymes involved are discussed, so that students can propose probable metabolic pathways for the given drugs. Students must also learn about original literature and its underlying thought processes and about methods used in metabolism studies such as in vitro and in vivo test models. Students must learn about, the basic requirements to analytical methods, so that they are able to plan metabolism studies and results and understand their clinical and toxicological relevance. Therefore the course is part of the general educational objective to impart expertise in planning and conducting chemical, pharmacological and pharmaceutical development, drug production and quality assurance of drugs and active pharmaceutical substances. The course contributes to general objectives about information and advice to health care personnel and the general population.

 

At the end of the course, students are expected to be able to:

Knowledge

  • know about phase 1 and phase 2 metabolic processes
  • know in which cell compartments and in which organs metabolism takes place
  • be able to describe the enzyme systems the organism uses to metabolize drugs
  • know about the function and significance of uptake and efflux transporters
  • know how to use in vitro metabolism models
  • know how to use in vivo metabolism models
  • know about the analytical chemical methods used
  • understand the significance of drug metabolism for the development of new drugs.

 

Skill

  • propose probable metabolic pathways for selected functional groups or drug groups

 

Competence

  • on the basis of the above knowledge be able to propose suitable in vivo and in vitro models and relevant analytical chemical methods for conducting drug metabolism studies.
  •  

•Lectures: 24 hours
•Laboratory exercises: 20 hours

  • Drug Metabolism in Drug Design and Drug Development, D. Zhang, M. Zhu and W.G. Humphreys (eds.), Wiley-Interscience (John Wiley & Sons, Inc.), Hoboken, New Jersey, USA, 2008, ISBN 978-0-471-73313-3.
  • Other course materials include relevant guidelines from the FDA and EMEA (ICH), articles relevant for lectures and instructions for laboratory exercises. These materials are available from the course homepage.

Course teaching is based on the assumption that students have basic competences in biochemistry, analytical chemistry, organic chemistry, pharmacology, toxicology and the drug development process, including, but not limited to, knowledge of the classes of chemical compounds, principles of chemical analyses plus knowledge of relevant apparatus, enzymes and enzyme kinetics, the composition and structure of eukaryotic cells, pharmacokinetics and pharmacodynamics.

ECTS
7,5 ECTS
Type of assessment
Written examination, 2 timer under invigilation
Continuous assessment
Assesment of individual written report and two-hour written multiple-choice test.

Examination design:
The examination is in two parts that will be weighted equally in the summative assessment. One part is the individually prepared written report dealing with the metabolism of a given drug. The report is based on several questions covered by the curriculum, which are to be answered using both primary literature and teaching materials and lectures.The second part consists of a two-hour written multiple-choice test. This will test basic knowledge covered by the curriculum (‘active knowledge’) including exercises, and questions to demonstrate general understanding of drug metabolism. The written examination contains several questions divided into three main themes and concerns metabolism as well as metabolic studies of a given drug. The three main themes are:
Literature studies of the metabolism of the drug,
Setting up an in vitro experiment to investigate/support the metabolism of the drug,
Setting up an in vivo experiment to investigate/support the metabolism of the drug. Each main theme consists of four questions (a-d). All questions are weighted equally.
Aid
All aids allowed

All written aids allowed.

Refer to the IT exams homepage link where the standard programs and IT tools available for the students’ disposal during IT exams under The Faculty of Health and Medical Sciences are listed.

During the exam, students will have access to MathType and the possibility to use a USB stick (for notes etc.)

Marking scale
7-point grading scale
Censorship form
No external censorship
Criteria for exam assessment

To achieve the grade 12 the student must be able to:

Knowledge

  • use clearly understandable and cohesive language and a convincing use of correct terminology for the field.
  • demonstrate an extensive knowledge of the literature about a given drug’s metabolism as well as the ability to analyse, take a critical position on and summarize the literature.
  • understand the importance of metabolism for pharmacokinetics, pharmacodynamics and toxicology.
  • demonstrate knowledge about phase 1 and phase 2 metabolic processes
  • understand which cell compartments and in which organs metabolism takes place
  • describe the enzyme systems the organism uses to metabolize drugs
  • describe the function and significance of uptake and efflux transporters
  • describe how to use in vitro metabolism models
  • demonstrate how to use in vivo metabolism models
  • know about the analytical chemical methods used
  • understand the significance of drug metabolism for the development of new drugs.

 

Skill

  • propose probable metabolic pathways for selected functional groups or drug groups
  • analyze metabolic enzymes’ (phase I and phase II plus transporter proteins) occurrence, function, nomenclature, substrates, and polymorfisms. Pharmacokinetic significance of the metabolism of the specific enzyme.
  • analyze the use of human and non-human in vitro and in vivo models, prerequisites for their use plus interpretation of results.

 

Competence

  • reflect academic knowledge in proposing suitable in vivo and in vitro models and relevant analytical chemical methods for conducting drug metabolism studies.

 

  • Category
  • Hours
  • Lectures
  • 24
  • Preparation
  • 88
  • Practical exercises
  • 20
  • Project work
  • 72
  • Exam
  • 2
  • English
  • 206