ADME PK - Polymorphism hw

(From NAPLEX practice exam, ignore portion not bold/underlined):

A 59-year-old man with acute coronary syndrome is admitted to the hospital for emergency percutaneous insertion of a coronary stent. Which of the following drugs might cause unexpected results based on the patient's CYP2C19 genotype?

Clopidogrel

If an individual is genotyped as CYP2C19 *2/*2, which phenotype would they be predicted to have?

poor CYP2C19 metabolizer

Interpret the plot for metoprolol. Of the three groups shown, which would be considered the fastest CYP2D6 metabolizers?

Group C

Consider the example in class of the metabolic conversion of codeine to morphine…

A genotype extensive CYP2D6 metabolizer has, in the past, taken the typical recommended dose of codeine and achieved typical pain reduction. 2 months after he was diagnosed with major depression and prescribed daily fluoxetine, he re-injured his knee and started again taking the same dose of codeine. However, the codeine did not relieve his pain. Which of the following is the most probable answer to explain why?

fluoxetine is a CYP2D6 strong inhibitor - in the presence of fluoxetine, less morphine will be produced from codeine, resulting in sub-therapeutic concentration of morphine

If an individual is genotyped as CYP2C19 ×1/*1, which phenotype would they be predicted to have?

extensive CYP2C19 metabolizer

Fluoxetine is metabolized in the liver primarily via N-demethylation to the active metabolite, norfluoxetine. Norfluoxetine has equal pharmacologic (therapeutic) activity to the parent compound.

CYP2D6 extensive metabolizers showed lower maximum plasma levels of fluoxetine and higher levels of norfluoxetine than did CYP2D6 poor metabolizers, but the total sum was equal in both CYP2D6 poor and extensive metabolizers.

Based on the above drug-information paragraph, what is the predicted therapeutic response to fluoxetine in poor vs. extensive CYP2D6 metabolizers?

CYP2D6 poor metabolizers should have equal level of therapeutic response to fluoxetine as compared to extensive metabolizers

If an individual is genotyped as CYP2C19 ×17/*17, which phenotype would they be predicted to have?

ultra-rapid CYP2C19 metabolizer

Consider the example in class of the metabolic conversion of codeine to morphine…

CYP2D6 ultra-rapid metabolizers are likely to have which response to a typical dose of codeine relative to the majority of the typical US population?

overdose response

T/F: Use the attached amitriptyline scheme and notice the metabolites that are labeled as therapeutically active or not active. An individual who is an ultra-rapid CYP2D6 metabolizer (relative to majority of population) would be at risk of having subtherapeutic response to a typical dose of amitriptyline.

true

Consider the example in class of the metabolic conversion of codeine to morphine…

CYP2D6 extensive metabolizers are likely to have which response to a typical dose of codeine relative to the majority of the typical US population?

same/normal level of analgesic response

T/F: Use the attached amitriptyline scheme and notice the metabolites that are labeled as therapeutically active or not active. An individual who is a poor CYP2D6 metabolizer (relative to majority of population) would be at risk of having subtherapeutic response to a typical dose of amitriptyline.

false

(NAPLEX style exam question from practice exams):
A 7-year-old child is brought to the emergency department with extreme sleepiness, confusion, shallow breathing, and pale or blue lips.  Her mother states that the girl was given codeine with acetaminophen because of severe bruising after a fall.  The physician suspects that drug metabolism is responsible for the adverse effect.

Which CYP is responsible for codeine metabolism, and which allele and metabolizer status combination could cause the above adverse effect?

CYP2D6×1×3, with ultra-rapid metabolizer phenotype

Consider the example in class of the metabolic conversion of codeine to morphine…

CYP2D6 poor metabolizers are likely to have which response to a typical dose of codeine relative to the majority of the typical US population?

no or diminished analgesic response