Pharmacogenomics

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Questions and Answers

Which type of metabolizer has the highest enzyme activity?

Extensive Metabolizers

Poor Metabolizers

Ultrarapid Metabolizers (correct)

Intermediate Metabolizers

What is the potential outcome for Poor Metabolizers when given a standard dose of a drug?

Complete drug tolerance

No effect on drug levels

Increased drug efficacy

Progressive increase in plasma drug levels (correct)

How do polymorphic alleles impact drug metabolism?

They can either decrease or enhance functionality. (correct)

They only affect drug transport mechanisms.

They are always detrimental to metabolism.

They have no effect on drug efficacy.

Which category of metabolizers demonstrates intermediate enzyme activity?

Intermediate Metabolizers Signup and view all the answers

What is a significant contributor to variability in drug response among individuals?

Genetic variations in enzymes Signup and view all the answers

What effect can over-expressed enzymes have on drug metabolism?

Increased drug toxicity Signup and view all the answers

Which of the following factors does NOT affect drug metabolism?

Consistent enzyme activity Signup and view all the answers

What is the primary clinical concern for patients identified as Ultrarapid Metabolizers?

Higher risk of drug toxicity Signup and view all the answers

CYP gene polymorphisms affect which aspect of pharmacokinetics?

Metabolism of drugs Signup and view all the answers

Which polymorphism represents the Wild Type allele in CYP enzymes?

*1 Signup and view all the answers

Which polymorphic alleles of CYP2C19 are associated with poor metabolism?

CYP2C19*2 and *3 Signup and view all the answers

What is the primary consequence for Ultra-Rapid Metabolizers (UMs) of CYP2D6 dependent drugs?

Increased risk of toxicity Signup and view all the answers

What does the FDA now recommend for patients being treated with warfarin?

CYP2C9 genotyping Signup and view all the answers

What is a significant effect of P-glycoprotein (P-gp) at the blood-brain barrier?

Minimizes drug concentrations drastically Signup and view all the answers

In terms of CYP2C9, which drug is particularly noted for requiring lower doses due to polymorphisms?

S-warfarin Signup and view all the answers

Which of the following describes the function of SLCO1B1 in drug metabolism?

Facilitates drug removal from hepatocytes Signup and view all the answers

Which of the following statements regarding CYP2D6 allelic variations is accurate?

CYP2D6 has high genetic variability with >75 identified alleles. Signup and view all the answers

What role do drug transporters like OAT1B1 play in pharmacokinetics?

Affect drug distribution and bioavailability Signup and view all the answers

What consequence do Poor Metabolizers (PMs) demonstrate regarding drug therapy?

Increased risk for adverse effects from standard doses Signup and view all the answers

What can be inferred about the genetic variability in enzyme expression?

It contributes to variable patient responses to medications. Signup and view all the answers

Study Notes

Genetic Variations and Drug Response

Genetic variations in enzymes and transporters have a significant impact on drug response, leading to variations in efficacy and toxicity.
Factors affecting metabolism include:
- Enzyme variability
- Receptor/transporter variability
Types of metabolizers include:
- Poor metabolizers (PM)
- Intermediate metabolizers (IM)
- Extensive metabolizers (EM)
- Ultrarapid metabolizers (UM)

Enzyme Variability

PMs have a loss of function, resulting in very low or no enzyme activity.
IMs have decreased enzyme activity.
EMs have overexpressed enzyme activity.
UMs have multiple gene copies resulting in increased enzyme activity.

Clinical Significance of Enzyme Variability

Genetic variations have been described for all major CYP enzymes involved in xenobiotic metabolism.
Variations can lead to reduced efficacy, therapeutic failure, and toxicity.
CYP polymorphisms are numbered based on the wild-type allele, which is *1.
Polymorphic alleles can increase or decrease functionality compared to the *1 allele.

CYP Polymorphisms: Examples

CYP2C9:
- Over 30 known alleles.
- Substrates include Losartan (active metabolite) and NSAIDs.
- *2 & *3 alleles lead to reduced functionality, affecting drug efficacy and risk of adverse effects.
- FDA recommends CYP2C9 genotyping for warfarin and celecoxib.
CYP2C19:
- Wild-type *1 allele is associated with EM.
- Major polymorphic alleles (*2, *3) result in PMs.
- *17 allele results in UMs.
- Variations affect PPI therapy for H. Pylori, clopidogrel (prodrug) efficacy, and citalopram/escitalopram efficacy.
CYP3A4:
- Plays a significant role in drug interactions (DDI) and drug-food interactions (DFI).
CYP2D6:
- Accounts for 2-5% of liver CYP expression.
- Responsible for metabolizing 25-30% of marketed drugs.
- High genetic variability with over 75 allelic variants.
- Multiple non-functional alleles have been identified.

Case Presentation: Codeine and CYP2D6

Mother: Heterozygous CYP2D62A & CYP2D62x2 gene duplication (UM).
Infant: Two functional CYP2D6 alleles *1/*2 (EM).
Infant died from respiratory depression.
The case highlights the clinical significance of genetic variability in CYP2D6-dependent drugs, leading to potential adverse effects for UMs and lack of efficacy for PMs.

Drug Transporters

Important drug transporters include P-gp and OAT1B1.
P-gp is located at the blood-brain barrier (BBB) and reduces CNS exposure to drugs.
SLCO1B1 (OATP1B1) is a hepatic transporter that removes drugs from circulation into hepatocytes.
Variations in drug transporter expression and function can lead to altered bioavailability, efficacy, toxicity, and CNS exposure.