FA806: Drug Transporters in ADME (5 ECTS)

STADS: 3854801

Level
Master's level course

Teaching period
The course is offered in the autumn semester.

Teacher responsible
Email: cun@sdu.dk

Additional teachers
steffansen@sdu.dk

Timetable
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Show personal time table for this course.

Prerequisites:
A bachelor degree in natural or health sciences in the area of pharmacy, biology, chemistry or medical related sciences.

Academic preconditions:
Students taking the course are expected to:

• Have knowledge, skills and competences of basic biochemistry, molecular biology, pharmacology and physiology.
• Have knowledge, skills and competences of pharmaceutics corresponding to a bachelor level.
• Have knowledge, skills and competences of procedures for working in a lab and lab safety.
• Skills to make simple calculations and statistical analyse

Course introduction
The aim of the course is that the students become able to define and classify drug transporting membrane proteins, and describe their role in determining ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties of drug substances. Furthermore, that the students can describe transporters role in tissue-specific drug delivery and exemplify how transporters impact on pharmacokinetic profiles of their drug substrates/inhibitors. Furthermore, that the students can describe the regulatory implications of transporter interactions and drug-drug interactions. Finally, the course aims the students can use experimental, IT approaches and gives a brief account of computer-based physiologically based pharmacokinetic (PBPK) modeling to calculate and derive drug absorption and transporter interactions.

The overall aim of the course, is thus that the participants are able to a) experimentally determine kinetic parameters related to transporters b) substantiate the role of drug transporters in overall ADMET properties of a drug compound, including predictions of bioavailability from in-vitro and in-situ experiments using PBPK modeling c) describe the regulatory aspects of transporter interactions of selected drug compounds d) discuss original scientific literature within the field.

The above-mentioned element are important for pharmacist working in the setting of drug discovery and drug development in the pharmaceutical industry as well as for clinical pharmacists and pharmacists working in public administration (e.g. Danish Agency of Medicines or Department of Health or Environment) that relate to the use and approval of drug products.

The course is a continuation of the knowledge, skills and competences acquired in bachelor courses FA502, FA503, FA504, SU5cc, BB524, BMB530, BMB504, and the master course in Drug transport and drug delivery systems.

The course builds on the knowledge, skills and competences acquired in the courses FA502, FA503, FA504, SU5cc, BB524, BMB530, BMB504, and the master course in “Drug transport and drug delivery systems”, and gives an academic basis for performing a Master Thesis project in the area related to ADME drug properties and transporters, that are part of the degree.

In relation to the competence profile of the degree it is the explicit focus of the course to:

• give competences required for participating in project groups working in drug development programs
• give competences required for discussing and approving the use of drug substances and drug products.
• give skills and competences such as for example in vitro-in vivo correlation and PBPK modeling discussing the interaction with drug transporters and the implications for drug delivery, pharmacokinetics and drug-drug interactions
• provide skills in substantiate and calculate the kinetics of drug transporters in barrier tissues and to conduct experiments with in-vitro barrier tissues as well as to interpret experimental flux data
• provide skills in conducting experimental approaches to investigate drug – transporter interaction
• provide competences in analyzing/discussion data involving transporters and transporter kinetics.
• provide skills in sound and critical communication of ADME properties and transporter findings.
• give knowledge about classifying transporters with regard to transporter type, structure, function, and expression in different tissues of the body
• give competences about planning, conducting and evaluating experiments aimed at investigating ADME properties and transport interactions.

Qualifications
FA8

Expected learning outcome
The learning objectives of the course is that the student demonstrates the ability to:

• To define when a drug is interacting with a transporter
• To calculate flux values, IC₅₀ values, K_m values and K_i values for passive and actively transported drugs, respectively
• To describe the role of transporters in ADME and pharmacokinetics
• To interpret/discuss experimental data on flux and transporter kinetic
• To predict, simulate and discuss when drug-transporter interacting result in drug-drug interactions or dose-dependent tissue accumulation or absorption
• To reflect/discuss about the consequences of drugs interacting with transporters or metabolising enzymes for tissue specific drug delivery and ADMET properties
• To suggest strategies for optimising ADMET properties based on knowledge about drug interaction with transporters and/or enzymes.

Subject overview
The course is based on lectures, lab exercises and e-classes that revolve around central subjects in the field of drug transporters in ADMET. The lectures cover a range of subjects:

• Overall ADMET properties
• Transporter kinetics
• Membrane transporter structure, function and expressiom
• The concepts of flux, permeability and carrier-mediated kinetics
• In vitro and in vivo methods for studying drug transport by membrane transporters the ADME concepts
• Pharmacokinetics and ADME
• Drug uptake and efflux transporters in the small intestine, liver and kidney and their interplay with metabolizing enzymes, drug uptake and efflux transporters in the blood-brain barrier
  and their role in drug delivery e.g to the CNS.
• PBPK modeling of the role of transporters in drug absorption and pharmacokinetics (Simcyp),
• FDA and EMA guidelines for transporter interactions.
• The e-classes are for calculation and estimation of kinetical parameters that are fundamental for understanding ADME and transporters. Thus students should be able to make basic calculations of e.g. flux and permeability.
• Making report based on exercises, that cover selected aspects of the curriculum:
  In vitro analysis of drug uptake transporter activity, In vitro analysis of drug efflux transporter activity exemplified by studies on the efflux pump P-glycoprotein, calculations of transporter kinetics from in vitro studies, calculations of transporter involvement in oral absorption using computer-based modeling.
  In the exercises, students work in groups of 2-4. Following the exercise, the results are used for preparing a written project report on the subject of the exercise, including background and literature studies. The reports will be performed by the same group that performed the practical exercise. The project reports has to be handed in to-, and approved by a course teacher. The results found must be reported clearly and precisely in keeping with the conventions in force in English-language journals.

Literature

• Bente Steffansen, Birger Brodin: Molecular Biopharmaceutics: Aspects of Drug Characterisation, Drug Delivery and Dosage Form Evaluation, Pharmaceutical Press, 2010.

Website
This course uses e-learn (blackboard).

Prerequisites for participating in the exam

1. Participation in all laboratory exercises is a prerequisite for taking part in exams a) and b). Pass/fail, internal marking by the teacher.

Assessment and marking:

1. Five reports based on lab work. Pass/fail, internal marking by teacher. (1 ECTS). (3854802).
2. Oral exam (30 minutes). Danish 7-mark scale, external marking.  (4 ECTS). (3854812).

Expected working hours
The teaching method is based on three phase model.
Intro phase: 22 hours
Skills training phase: 26 hours, hereof:
 - Tutorials: 6 hours
 - Laboratory exercises: 20 hours

Educational activities Study phase: 82 hours
Educational form
Activities during the study phase:

• Reading of text book material and scientific paper
• Calculation and presentation of results obtained during the laboratory work
• Evaluation of experimental obtained data
• Preparation of scientific rapport based on the lab work

Language
This course is taught in English.

Course enrollment
See deadline of enrolment.

Tuition fees for single courses
See fees for single courses.