How to Better Understand the Results of Your Genetic Test - Annette Youssef Pharm D. Candidate 2010

DRUG METABOLISM: Drug Metabolism: refers to the rate (how rapidly or slowly) your body can change a drug from one form into another form The cytochromes or CYPs are the metabolic factories in the liver and intestine

CYOCHROMES or CYPs Different CYPs metabolize different drugs There are several CYPs Important CYPs that have different genetic variations are CYP2C9, CYP2C19 and CYP2D6. They process about half of commonly prescribed medicines.

WHAT ARE ALLELES An allele is one member of a pair or series of genes that occupy a specific position on a specific chromosome Different combinations of alleles will produce a poor, intermediate, extensive (normal) or ultrarapid metabolizer

DRUG FORMS: Drugs are designed in 2 forms: 1.) Active Drug Form: Drug is designed to work after it enters your body 2.) Prodrug (Inactive Drug Form): Drug will not work until it has been metabolized (must be changed to the active form)

GO TO NEXT SLIDE TO SEE HOW YOUR BODY REACTS TO THE DIFFERENT DRUG FORMS

ACTIVE DRUG VS. INACTIVE DRUG Active Drug: metabolism Works in your body Ready to be removed from your body Prodrug (Inactive Drug): metabolism metabolism No effect in your body Works in your Ready to be removed body from your body

DRUG METABOLISM: When you metabolize the 2 different versions of a drug (active form or inactive form) there are 2 different consequences: 1.) Active Form: Your body changes the active form of a drug into a form that makes it easier to remove from your body- generally an inactive form 2.) Inactive Form: Your body changes the inactive form into a form that works in your body

INTERPRETING YOUR RESULTS You are now ready to interpret the results of your genetic test:

YOUR RESULTS There are 4 possibilities for each gene that is tested: 1.) Poor Metabolizer of CYP2D6, CYP2C9, CYP2C19Poor Metabolizer of CYP2D6, 2.) Intermediate Metabolizer of CYP2D6, CYP2C9, CYP2C19 3.) Extensive Metabolizer (Normal metabolizer) of CYP2D6, CYP2C9, CYP2C19Extensive Metabolizer 4.) Ultra-rapid Metabolizer of CYP2D6Ultra-rapid Metabolizer of CYP2D6 * Click on the metabolizer status that applies to you

WHAT ALLELES MAKE A POOR METABOLIZER *1 is an allele with normal activity *2 is an allele with diminished activity You inherit one allele from each of your parents If you inherit *1/*1 you are a Normal Metabolizer If you inherit *2/*2 you are an Poor Metabolizer

POOR METABOLIZER Your cytochrome genes control the amount of cytochrome protein If you are a poor metabolizer, your cytochromes have no or little cytochrome protein

POOR METABOLIZER Poor Metabolizer: Your body changes the drug to a different form very slowly or not at all (rate: 0-25% compared to normal) How your body will react to: 1.Active Drug:Active Drug 2.Prodrug (Inactive Drug):Prodrug (Inactive Drug):

POOR METABOLIZER + ACTIVE DRUG Your body will not be able to, or will change the active drug to a form that is ready to be removed from your body very slowly: Result: The drug will stay in your body for a longer period of time or you will have more drug reaching your system in a shorter period of time and levels of the active drug may be increased Drug Effect: You will experience symptoms similar to overdosing on a drug Go to next slide for example:

POOR METABOLIZER + ACTIVE DRUG: Example: Fictional drug caffeinolam If you are taking a drug called caffeinolam and you are a poor metabolizer: 1.) You will experience the effects of caffeinolam for a longer period of time or your levels of caffeinolam will be higher than someone who is a normal metabolizer 2.) You may experience exaggerated effects of caffeinolam: such as a really rapid heart beat, extreme wakefulness, anxiety, sweating, etc.

ACTION: Do not change your current therapy without talking to your healthcare provider first. They may have already taken your results into account as well as many other factors integral to your therapy. Your healthcare provider may tell you to decrease dose of drug Increase the time between doses (eg: take the drug every other day instead of every day) Avoid the drug altogether Back to Poor Metabolizer Back to Results

POOR METABOLIZER + PRODRUG (INACTIVE DRUG) Your body will not be able to, or will not change the inactive form of the drug to the active form of the drug at an extremely slow rate Levels of the prodrug (inactive form) will be increased and the active form decreased Result: You will not experience the effects or the benefits of the drug you are taking Go to next slide for example:

POOR METABOLIZER + PRODRUG (INACTIVE DRUG): Example: Fictional Drug teaolam If you are taking teaolam and you are a poor metabolizer, the active form of the drug is teaozide Levels of teaolam will increase and levels of teaozide will be decreased or absent You will not experience the effects of teaozide such as wakefulness and alertness

ACTION: Do not change your current therapy without talking to your healthcare provider first. They may have already taken your results into account as well as many other factors integral to your therapy Back to Poor Metabolizer Back to Results

INTERMEDIATE METABOLIZER Intermediate Metabolizer Your body changes the drug to a different form at a slower rate than normal (~50% of that of normal metabolizers) How your body will react to: 1.) Active Drug:Active Drug: 2.) Prodrug (Inactive Drug):Prodrug (Inactive Drug):

WHAT ALLELES MAKE AN INTERMEDIATE METABOLIZER *1 is an allele with normal activity *2 is an allele with diminished activity You inherit one allele from each of your parents If you inherit *1/*1 you are a Normal Metabolizer If you inherit *1/*2 you are an Intermediate Metabolizer

INTERMEDIATE METABOLIZER + ACTIVE DRUG: Your body will change the active drug to a form that is ready to be removed from your body at a rate that is half of that of a normal metabolizer: Result: The drug will stay in your body for an extended period of time or you will have more drug reaching your system in a shorter period of time Drug Effect: You may experience symptoms similar to a minor overdosage Go to next slide for example:

INTERMEDIATE METABOLIZER + ACTIVE DRUG: Example Fictional Drug caffeinolam If you are taking caffeinolam and you are an intermediate metabolizer: 1.) You will experience the effect of caffeinolam for a longer period of time: 4 hours vs. 2 hour if you metabolized caffeinolam normally 2.) You may experience toxic effects of caffeinolam: such as a really rapid heart beat, extreme wakefulness, anxiety, sweating, etc. These would mimic the symptoms of an overdosage: having too much caffeinolam in a short period of time

ACTION: Do not change your current therapy without talking to your healthcare provider first. They may have already taken your results into account as well as many other factors integral to your therapy They may tell you to: 1. Decrease dose of drug 2. Increase the time between doses (eg: take the drug every other day instead of every day) 3. Avoid the drug altogether Back to Intermediate Metabolizer Back to Results

INTERMEDIATE METABOLIZER + PRODRUG (INACTIVE DRUG): Your body will change the inactive form of the drug to the active form of the drug at a slower rate than normal ~50% Result: You will experience some of the benefits of drug therapy, but perhaps not maximally Go to next slide for example:

INTERMEDIATE METABOLIZER + PRODRUG (INACTIVE DRUG): Fictional drug teaolam If you are taking teaolam and you are an intermediate metabolizer: Less of the active agent teaoside will be be available You will experience only some of the effects of Teaolam such as alertness and wakefulness

ACTION: To seek the benefits of drug therapy: Do not change your current therapy without talking to your healthcare provider first. They may have already taken your results into account as well as many other factors integral to your therapy They may tell you to: 1.) Increase the dose of the drug may be an option 2.) An alternative drug may be chosen that would have an increased likelihood of working Back to Intermediate Metabolizer Back to Results

EXTENSIVE METABOLIZER Extensive Metabolizer Your body metabolizes drug at a normal rate (not too fast and not to slow: just right)

WHAT ALLELES MAKE AN EXTENSIVE OR NORMAL METABOLIZER *1 is an allele with normal activity *2 is an allele with diminished activity You inherit one allele from each of your parents If you inherit *1/*1 you are a Normal Metabolizer

ACTION: No changes to your drug regimen are warranted at this time You represent the population that responds to drug therapy at the recommended doses Back to Results

WHAT ALLELES MAKE AN ULTRARAPID METABOLIZER *1 is an allele with normal activity You inherit one allele from one parent and more than one allele from another parent If you inherit *1/*1 you are a Normal Metabolizer If you inherit *1/*1 duplication you are an Ultrarapid Metabolizer

ULTRA RAPID METABOLIZER Ultra Rapid Metabolizer Your body changes the drug to the inactive form at a very rapid rate How your body will react to: 1.Active Drug:Active Drug: 2.Prodrug (Inactive Drug):Prodrug (Inactive Drug):

ULTRA RAPID METABOLIZER + ACTIVE DRUG: Your body will change the active drug to a form that is ready to be removed from your body at a very quick rate: Result: The drug will be removed from your body very quickly and will have only a short time to exert its effects Drug Effect: You may have a decreased response to your drug and its benefits

ULTRARAPID METABOLIZER + ACTIVE DRUG: Example Fictional Drug caffeinolam If you are taking caffeinolam and you are an Ultrarapid metabolizer: 1.) You will experience the effect of Caffeinolam for a shorter period of time: 1 hour vs. 3 hours if you metabolized coffee normally 2.) You will not experience the maximum effect of caffeinolam:

ACTION: To seek benefits of drug therapy: Do not change your current therapy without talking to your healthcare provider first. They may have already taken your results into account as well as many other factors integral to your therapy Your provider may tell you to 1.) Increase the dose of the drug 2.) Decrease the dosing interval may be an option (take the drug twice a day vs. once a day) 3.) An alternative drug may be chosen that would have an increased likelihood of working Back to Ultra Rapid Metabolizer Back to Results

ULTRA RAPID METABOLIZER + PRODRUG (INACTIVE DRUG): Your body will change the inactive form of the drug to the active form at a very rapid rate Result: There will be a greater amount of active drug in your body in a shorter period of time Drug Effect: You will experience symptoms similar to overdosing on a drug Go to next slide for example:

ULTRA RAPID METABOLIZER + PRODRUG (INACTIVE DRUG): Example Fictional Drug caffeinolam If you are taking caffeinolam and you are an ultrarapid metabolizer: 1.) You will experience the effect of caffeinolam in a shorter period of time: 5 min. vs. 30 min if you metabolized caffeinolam normally 2.) You may experience toxic effects of caffeinolam: such as a really rapid heart beat, extreme wakefulness, anxiety, sweating, etc. These would mimic the symptoms of an overdosage: having too much caffeinolam in a short period of time

ACTION: Do not change your current therapy without talking to your healthcare provider first. They may have already taken your results into account as well as many other factors integral to your therapy 1. Decrease dose of drug 2. Increase the time between doses (eg: take the drug every other day instead of every day) 3. Avoid the drug altogether Back to Ultra Rapid Metabolizer Back to Results