bps 325 exam3

Covering topics from last third of class. exam 3 is comprehensive so all info from semester will be on exam

What is the difference between enzyme inducers and enzyme activators?

Inducers increase the amount of enzyme (expression of enzyme)

Activators increase the catalytic turnover of each active site (activity of enzyme)

What is meant by “activity”?

Catalytic rate or turnover

• Number of product molecules formed per active site per minute

Define enzyme inhibitor

Something that decreases catalytic turnover of each active site (decreases activity)

Define enzyme activator

Something that increases catalytic turnover of each active site (increases activity)

Define enzyme inducer

Something that increases the amount of enzyme present (expression)

Define enzyme suppressor

Something that decreases the amount of enzyme present (expression)

How do inhibitors impact clearance rate?

Decreases clearance

How do inducers impact clearance rate?

Increases clearance

What is the FDA specific definition of a CYP substrate with “narrow therapeutic range”

A CYP substrate drug whose exposure-response indicates that increases/decreases in their exposures may lead to serious safety concerns

What is the FDA specific definition of a sensitive CYP substrate?

A CYP substrate drug whose plasma AUC values have been shown to increase 5-fold or higher with any known strong CYPxxx inhibitor

How does the FDA define a strong CYP inhibitor?

• Cause a ≥ 5-fold increase in the plasma AUC values

  • Or cause more than an 80% decrease in clearance (volume of blood cleared of drug/time)

Of any CYP substrate in clinical evals, not limited to sensitive CYP substrates

How does the FDA define a moderate CYP inhibitor?

• Cause a ≥2 fold, but <5-fold increase in AUC values

  • Or 50-80% decrease in clearance of sensitive substrates

    • When the inhibitor was given at the highest approved dose and the shortest dosing interval in clinical evaluations

How does the FDA define a weak CYP inhibitor?

• Caused a ≥1.5-fold but <2 fold increase in AUC values

• Or 20-50% decrease in clearance of

  • sensitive CYP substrates when the inhibitor was given at the highest approved dose and the shortest dosing interval in clinical evaluations

What statin is cleared by CYP2C9

Fluvastatin

Which statins are primarily cleared by CYP3A4 metabolism

• Lovastatin

• Atorvastatin

• Simvastatin

• Cerivastatin

Why is lovastatin and simvastatin so greatly effected by cyclosporine?

Inhibits P-glycoprotein transporter-mediated excretion of statins from hepatocytes. Moderate CYP3A4 inhibitor

• Lovastatin and simvastatin are substrates for both CYP3A4 and P-gp

How do enzyme inhibitors decrease rate of catalysis?

Directly binding to the enzyme

• Reversible

  • Competitive, lowers Km

  • Non-competitive, lowers Vmax

    • Effects only last until inhibitor is cleared

• Irreversible

  • Need new enzyme to be synthesized

    • & effect lasts until new enzyme is synthesized

How do enzyme inducers work? How long does the effect of inducers last?

They increase the amt of enzyme present

• Most inducers are ligands for transcription factors

• Ligand binds to partner transcription factor → partner binds to promotor element → promotes expression of genes responsible for enzyme synthesis

  • Increased transcription of gene = more mRNA = more protein (enzyme) synthesis

MORE ENZYME=GREATER CLEARANCE OF DRUG. Effect generally lasts for several days; dependent on the degradation rate of enzyme.

Why is CYP2D6 genotype/phenotype important?

• Activity is extremely variable due to 50+ genetic variations

What makes someone an ultra rapid CYP2D6 metabolizer? How does this impact metabolism?

More than 3 copies of active 2D6 gene

• Extremely high 2D6 activity

What makes someone an extensive CYP2D6 metabolizer? How does this impact metabolism?

2-3 copies of 2D6 gene.

Displays typical 2D6 activity

How does being an intermediate 2D6 metabolizer impact activity?

Decreased CYP2D6 activity

What makes someone a poor CYP2D6 metabolizer? How does this impact metabolism?

Two nonfunctional 2D6 alleles

no 2D6 in liver

Has abolished activity/no activity

How are CYP 2D6 extensive metabolizers impacted by 2D6 inhibitors

2D6 EMs are poor metabolizers when in the presence of 2D6 inhibitors

How does CYP2D6 ultra rapid metabolism impact the synthesis of codeine? Clinical implications?

Rapid conversion into active metabolite (morphine)

• Higher than expected serum morphine levels

• May have life-threatening/fatal respiratory depression and experience signs of OD

How does CYPD2D6 genotype alter metoprolol effects

Impact on HR is dependent on the number of copies of active 2D6

How can 2D6 inhibition further reduce 2D6 metabolism?

Use of a strong 2D6 inhibitor can shift a 2D6 extensive metabolizer into a 2D6 poor metabolizer

• Doses of medications metabolized by 2D6 with a low TI should be adjusted if a patient is taking a 2D6 inhibitor

What genotype is CYP2C19 ultra rapid metabolizer

One or two *17 alleles (CYP2D6*17)

What phenotype is CYP2D6*17

Ultra rapid metabolizer

What phenotype is CYP2C19*1/*1

Extensive metabolizer

What genotypes are intermediate CYP2C19 metabolizers

*1 on one allele, *2 on the other

*1 on one allele, *3 on the other

What phenotype is this combo: CYP2C19*1 & CYP2C19*3

Intermediate CYP2C19 metabolizer

What phenotype is this combo: CYP2C19*1 & CYP2C19*2

Intermediate CYP2C19 metabolizer

What genotype is a poor CYP2C19 metabolizer

Two *2 alleles

OR

Two *3 alleles

What phenotype is this combo: CYP2C19*3 & CYP2C19*3

Poor CYP2C19 metabolizer

What phenotype is this combo: CYP2C19*2 & CYP2C19*2

Poor CYP2C19 metabolizer

Describe relationship between Prasugrel and CYP gene variation

Genetic variation has no impact on pharmacokinetics of Prasugrel

Describe warfarin metabolism

• Almost entirely cleared by metabolism

  • 90% of S-enantiomers 2C9 → 7-OH Warfarin

  • 60% of R-enantiomers 3A4 + 1A2 → 10-OH Warfarin

  • Minor metabolites by 2C19, 2C8, 2C18

7- and 10-OH Warfarin inhibit 2C9. Prevents formation of 7-OH metabolite