COMPUTER-BASED TUTORIALS IN DRUG METABOLISM

Patrick J. Davis and Justin Briggle, College of Pharmacy, University of Texas, Austin, TX 78712-1074

INTRODUCTION:

Student comprehension of drug metabolism is fundamental to understanding multiple factors responsible for drug disposition (ADME), metabolically-based drug-drug interactions, and pharmacogenetic differences in drug disposition. From an introductory standpoint, this requires an integration of (a) organic functional group recognition, (b) knowledge of phase-1 and phase-2 modifications targeting those functional groups (c) the specific enzymes involved, and (d) fundamental reaction mechanisms common to these bioconversions. With mastery of these basic concepts, a target ability is for students to be able to examine any drug molecule and make logical predictions of the full composite of potential phase-1 and phase-2 metabolites for that drug, resulting in a hypothetical "metabolic tree" (see Figure 1).

Drug metabolism is covered in our Introductory Medicinal Chemistry course (PHR 143M) and reinforced in the associated Laboratory course (143P). Currently, the laboratory exercise is conducted by assigning each one of the 25 students a single enzyme activity (requiring them to recognize a specific functional group and metabolic reaction), and cycling through the class until the full metabolic tree is constructed. While largely successful, this method has the limitation that each student is responsible for only one enzyme/reaction. In addition, students have requested computer based-tutorials to broaden their exposure and reinforce concepts.


OBJECTIVES:

This project was undertaken to develop a computer-based tutorial for reinforcing and integrating these basic concepts, and to help students develop the ability to predict routes of drug metabolism based on functional groups present. The specific objectives (ongoing) were as follows:


METHODS:

  • Phase-1: [funded by a Fast-Tex Technologies Grant]. Macromedia Flash® was found to provide an authoring environment that was flexible, dynamic, accepted input from chemical structure files (ChemDraw®), and allowed for export as platform-independent movie files to be viewed in Flash Players and/or standard web browsers.

    In the Macromedia Flash® authoring environment (see Figure 2) a multi-layered 'stage' is used to integrate graphics elements (e.g., chemical structures & animations), interactive buttons (e.g. functional group identifiers), and action scripting (e.g., enzyme identification) for the production of highly interactive, platform-independent movies. We initially started with Flash 5.0, and have now moved to Flash-MX® for this project.

  • Phase-2: Haplophytine was chosen as a metabolically complex example (Figure 1) for feasibility testing. The Flash® .fla file (Figure 2) consists of multiple layers which integrate the animations (motion of parent molecules and metabolites), interactive buttons placed on the functional groups to direct movie flow, and pull-down menus to query students on enzymes, reaction pathways, and product names. The entire movie is exported as an swf file to be viewed in a Flash Player.

    Figures 3, 4, and 5 display a single pathway example from this file:


    RESULTS:

    A Flash®-based, platform-independent tutorial was constructed to address the needs described. The tutorial uses animation to simplify viewing as a complex metabolic tree emerges. Each step in the construction of the metabolic tree involves student queries in the four basic knowledge areas described in the Introduction. Educational assessment of the tutorials will be undertaken with the Fall-02 offering of the laboratory.


    IMPLICATIONS:

    These tutorials will allow students to work independently or in small groups to review and integrate the knowledge areas required for understanding drug metabolism. Simple to very complex drug molecules can be analyzed, resulting in the generation of very simple to very complex metabolic trees. [Supported by a Fast~Tex Grant from The University of Texas Center for Instructional Technologies].