Drug Metabolism and Disposition updated by alicejenny


                    Drug Metabolism and Disposition (updated 10/13/08)
                                       ECP 5620
                                        3 Credits
                                  Spring Semester 2009

Course Coordinator:        Timothy S. Tracy, Ph.D.
                           Experimental and Clinical Pharmacology
                           7-168 Weaver-Densford Hall
                           Phone: 612-625-7665 Fax: 612-625-3927
                           E-mail: tracy017@umn.edu

Participating Faculty:     Rory Remmel, Ph.D.
                           Medicinal Chemistry
                           7-125C Weaver-Densford Hall
                           Phone: 612-624-0472
                           E-mail: remme001@umn.edu

                           Cheryl Zimmerman, Ph.D.
                           9-149B Weaver-Densford Hall
                           Phone: 612-624-4611
                           E-mail: zimme005@umn.edu

                           William Elmquist, Ph.D.
                           Associate Professor
                           9-127D Weaver-Densford Hall
                           Phone: 612-625-0097
                           E-mail: elmqu011@umn.edu

Room and Times:            Room TBA
                           Monday, Tuesday, Thursday 8-9 AM

Learning Objectives:       At the conclusion of the course, the student will be able to:
                           1. Describe the oxidative (Phase I) and conjugative (Phase II) enzymes
                               systems involved in human drug metabolism and disposition.
                           2. Explain the various in vitro models used to evaluate the metabolism of
                               a drug or new chemical entity and the pros and cons of each model
                           3. Describe the factors involved in conducting in vivo drug metabolism
                               studies and the strengths and limitations of in vivo studies.
                           4. Explain the components used to predict in vivo drug disposition from in
                               vitro data.
                           5. Develop a presentation, using an example from the literature, describing
                               a model study of human drug metabolism.
Textbook:                Recommended (but not required):
                         Human Drug Metabolism: An Introduction, Michael D. Coleman, Wiley,
                         Inc., 2005. ISBN: 0-470-86353-6

                         Handouts will be provided by instructor.

Prerequisites:           Graduate standing or consent of instructor.

Course Requirements:     Take exams and develop an ~20 minute presentation to be given to the class
                         on a model drug metabolism study.

Exams and assignments:   Three take home exams consisting of short answer/essay questions. Exams
                         will each be worth 30 points (30% of the final grade). One presentation
                         worth 10 points (10% of final grade) will be required and will consist of a
                         short (~20 minute) presentation describing a model study from the primary
                         literature that demonstrates usage of a method or concept covered
                         previously in the semester (instructor will OK papers to be presented).

                          One hour of “release time” will be given for each exam and the exams will
                         be due at the beginning of the next class period follow the respective
                         “release days”. In order for the exam turn in time to be changed, a 100%
                         positive vote by students in the class will be required.

Grading Policy:          A total of 100 points can be obtained on exams and presentation. A
                         percentage will be calculated based on the number of points each student
                         earns over the semester. Grades will be assigned as follows:

                         90-100% A, 80-89% B, 70-79% C, 65-69%D, <65% F

Academic Misconduct:     Academic misconduct is any unauthorized act which may give a student an
                         unfair advantage over other students, including but not limited to:
                         falsification, plagiarism, misuse of test materials, receiving unauthorized
                         assistance and giving unauthorized assistance. Each student will be
                         required to do their own work on all take-home exams and the presentation.
                         Each student will be asked to sign a cover sheet on each exam stating that
                         these guidelines have been followed.

Make-up Policy:          A make-up exam or rescheduling of a presentation will be allowed only
                         under one of the following circumstances: illness, verified by a note from a
                         doctor; a family emergency, verified by a note from the professional person
                         in attendance; a University-sponsored event, verified by a note from the
                         leader of the sponsoring organization.

Disability Accommodations:      Any student with a documented disability (e.g. physical learning,
                                psychiatric, vision, hearing etc.) who needs to arrange reasonable
                                accommodations must contact the Course Director (625-7665) and
                                Disability Services (626-1333) at the beginning of the semester. All
                                discussions will remain confidential.

Course Evaluation:       Scheduled at the beginning of class on the last regular class meeting period.
Class Schedule
 Lecture #          Dates                           Topic                         Instructor
     1       Jan. 21        Introduction to Drug Metabolism                        Remmel
                             Purpose of drug metabolism
                             Types and chemistry of drug metabolism processes
                                 o Oxidative
     2       Jan. 23        Introduction to Drug Metabolism, cont’d.               Remmel
                             Types and chemistry of drug metabolism processes
                                 o Reduction
                                 o Conjugation
                                 o Hydrolysis—Non-enzymatic
                             Reactive Intermediates

     3       Jan. 26        Sites of Drug Metabolism and First-Pass Effects        Remmel
                             Hepatic
                             Extra-hepatic
                             Unique role of the gut
                             First-pass metabolism
                                  o Principles
                                  o Avoidance
                                  o Relevance

     4       Jan. 28        Conjugative (Phase II) Enzymes                         Remmel
                             Function (overall)
                             Glucuronosyl Transferases—Mechanism & Regulation
                             Sulfotransferases—Mechanism & Regulation
                             Glutathione S-Transferases—Mechanism & Regulation
                             Acetyltransferases—Mechanism & Regulation
                             Methyltransferases—Mechanisms & Regulation
                             Others
                             Regional localization

     5       Jan. 30        Conjugative (Phase II) Enzymes (continued)             Remmel

     6       Feb. 2         Conjugative (Phase II) Enzymes (continued)             Remmel

     7       Feb. 4         Other Metabolizing Enzymes                             Remmel
                             Flavin Mono-oxygenases
                             Epoxide Hydrolases
                             Esterases
                             Amidases
                             Others
     8       Feb. 6         Cytochrome P450 Enzymes                                 Tracy
                             Intro to catalytic cycle/function
                             Isoforms
                                  o Substrate specificity
                                  o Inhibitors
                                  o Inducers
                             Regional localization of isoforms
     9       Feb. 9         Cytochrome P450 Enzymes (continued)                     Tracy
  10     Feb. 11   Transporters                                          Elmquist
                    Concept & Role in Body
                    Tissue Localization
                    Classes of Transporters
                    Effect on Drug Disposition
                    Regulation

  11     Feb. 13   Transporters (continued)                              Elmquist

  12     Feb. 16   Case Study (End of exam #1 material)                    Tracy
                   Exam will be handed out this day and due Feb. 23

Exam 1   Feb. 18   No class - Take-home exam (release day)               Instructors
                   Exam due Feb. 23

  13     Feb. 20   Pharmacogenetics & Drug Metabolism                      Tracy
                    Genetics & Inheritance
                    Polymorphisms vs. Mutations
                    Cytochrome P450 Polymorphisms
                      o P450 2D6
                      o P450 2C19
                      o P450 2C9
                      o P450 3A4/5
                    Relationship of polymorphisms to disease
                    Role of polymorphisms in clinical study design
                      o Effect on kinetic and metabolism studies
                      o Evaluation of role of polymorphisms in disease

  14     Feb. 23   Pharmacogenetics & Drug Metabolism (continued)          Tracy

  15     Feb. 25   Pharmacogenetics & Drug Metabolism, (continued)        Remmel
                    Phase II enzyme and FMO polymorphisms
                      o Acetyltransferases
                      o UGT’s
                      o Sulfotransferases
                      o Methyltransferases
                      o FMOs
                    Relationship of polymorphisms to disease
                    Role of polymorphisms in clinical study design
                      o Effect on kinetic and metabolism studies
                      o Evaluation of role of polymorphisms in disease

  16     Feb. 27   Pharmacogenetics & Drug Metabolism, (continued)        Remmel

  18     Mar. 4    In Vitro Metabolism Methods, (continued)               Remmel
                     Hepatocytes
                       o Concept
                       o Preparation (Fresh vs. Frozen)(Primary vs.
                       o Pros & Cons
                     Tissue Slices
                       o Concept
                       o Pros & Cons
                     Perfused Organs
                        o Concept
                    Pros & Cons
  19      Mar. 6    In Vitro Phenotyping & Kinetics                         Tracy
                     Phenotyping
                        o Expressed Enzyme vs. Selective Inhibitors vs.
                            Monoclonal antibodies
                        o Probe substrate selection
                     Enzyme Kinetics
                        o Assurance of linearity/Methodology
                        o Parameter estimation
                        o Caveats
  20      Mar. 9    Inhibition Kinetics                                     Tracy
                     Role in predicting drug interactions
                     Competitive inhibition
                     Non-Competitive inhibition
                     Un-Competitive inhibition
                     Mixed inhibition
                     Parameter estimation (Graphical and non-linear
                     Methodology of experiments
                     Caveats

  21      Mar. 11   Mechanism-Based Inhibition                              Tracy
                    • Clinical relevance
                    • Time-dependence
                    • Mechanisms/Types
                    • Conduct of Experiments
                    • Caveats

  22      Mar. 13   Case Study (End of Exam #2 material)                    Tracy
                    Exam will be handed out on March 23, due March 30

Exam #2   Mar. 23   No Class - Take-home Exam (release day) Exam due on   Instructors
                    Mar. 30

  23      Mar. 25   Atypical Enzyme Kinetics                                Tracy
                     Auto-activation (Sigmoidal)
                     Biphasic Kinetics
                     Substrate inhibition
                     Hetero-activation
                     Substrate-dependent inhibition
                     Mechanism for occurrence
                     Caveats

  24      Mar. 27   Enzyme Induction                                       Remmel
                              Concept
                              Types of induction
                                     o Protein synthesis
                                     o Enzyme stabilization
                              Time course
                              Mechanisms of induction
                                     o Orphan nuclear receptors (PXR,
                                           GR, CAR, RXR, HNFα)
                                  Isoform-specific induction
                                  Conduct of experiments
                                  Caveats

  25      Mar. 30   Enzyme Induction (continued)                              Remmel

  26      Apr. 1    In Vitro-In Vivo Correlations                            Zimmerman
                     Concept
                     Choice of in vitro system
                     Scale-up
                     Factors to consider
                     Methods
                     Assumptions
                     Effect of atypical kinetics
                     Caveats

  27      Apr. 3    In Vitro-In Vivo Correlations (continued)                Zimmerman

  28      Apr. 6    In Vivo Drug Metabolism Studies                            Tracy
                     Rationale
                     Patient Experimentation Issues
                     Kinetics—parent & metabolite
                     Inhibition studies
                     Induction studies
                     Biofluid sampling (Plasma vs. Urine vs. Feces, etc.)
                     Mass Balance Studies (Radioactivity)
                     Metabolite Identification and Kinetics
                     Dose-ranging Studies (esp. First-dose in humans)
                       Pharmacogenetics & Genotyping

  29      Apr. 8    In Vivo Drug Metabolism Studies (continued)                Tracy

  30      Apr. 10   In Vivo Drug Metabolism Studies (continued)                Tracy

  31      Apr. 13   Predicting Drug Disposition & Drug Interactions in         Tracy
                    Drug Discovery and Drug Development
                     Metabolic Stability
                     Isoform Involvement
                     Inhibition constants & inhibition potential

  32      Apr. 15   Predicting Drug Disposition & Drug Interactions in         Tracy
                    Drug Discovery and Drug Development, cont’d

  33      Apr. 17   Case Study (End of material for Exam #3)                  Tracy &
                    Exam will be handed out this day                          Remmel

Exam #3   Apr. 20   No class - Take-home exam (release day)                  Instructors
                    Exam due April 24

  34      Apr. 24   Seminal Paper Discussions                                 Tracy &
                       PhRMA In Vitro – In Vivo Position Paper               Remmel
35   Apr. 27   Seminal Paper Discussions                                    Tracy &
                   FDA Probe Drug Paper                                    Remmel

36   Apr. 29   Seminal Paper Discussions                                    Tracy &
                   PhRMA Pharmacogenomics Position Paper                   Remmel

37   May 1     Student Presentations                                        Tracy &
                15-20 minute presentations on primary literature related   Remmel
                  to one of the lecture topics
                  o Coordinator will OK paper

38   May 4     Student Presentations (continued)                            Tracy &

39   May 6     Student Presentations (continued)                            Tracy &

40   May 8     Student Presentations (continued)                            Tracy &

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