Pharmacology 3620 Lecture Notes - Lecture 9: Vitamin K Epoxide Reductase, Cyp2D6, Pharmacogenetics

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Lecture 009: Pharmacogenetics II
Objectives
Describe clinically important examples in pharmacogenetics
Precision Medicine
Emerging approach for disease prevention and treatment that takes into account
people’s individual variations in genes, environment and lifestyle
Pharmacogenetics - Practical Examples
Phase I Drug Metabolizing Enzymes
CYP2D6
CYP2C9
Drug Transport Proteins
OATP1B1
Phase II Drug Metabolizing Enzymes
TPMT
UGT1A1
Drug Targets
β1 adrenergic receptor
Vitamin K epoxide reductase complex I
CYP2D6
Metabolizes about 25% of ALL drugs on the market
Have SNPs, IN/DELS, CNVs variants
Over 90 knowl allelic variants
Nomenclature for polymorphisms are denoted by “*”
*1 is usually the wild-type sequence
Can have multiple polymorphism with 1 *
CYP2D6 Phenotype
A person’s highest functioning CYP2D6 allele predicts their CYP2D6 phenotype
Patients with different metabolization have very different dose requirements
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The Gene-Dose Effect
Nortriptyline is an antidepressant drug
metabolized by CYP2D6
Patients with 0-1 functional CYP2D6 alleles
will have much higher exposure to the drug
than normal people
Multiple copies of CYP2D6 (duplication) is
relatively rare in Caucasians, but is fairly high
in frequency in some East African populations
Need greater dose to get the same
therapeutic effect
How do we give drug when there is such high
variance?
Drug company tests a population and
choose a dose that most people
receive therapeutical effect (with low
side effects) and call it a day
Case Study #1
Healthy boy was delivered
After birth mother was prescribed a combination tablet containing 30 mg of codeine and
500 mg of acetaminophen (taken twice daily)
1 week after: baby appeared lethargic
13 days after birth: baby was found dead
Codeine
An analgesic used to minor to moderate pain
Codeine itself has weak analgesic activity
It’s a PRODRUG
Metabolite has the pharmacological activity
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Document Summary

Emerging approach for disease prevention and treatment that takes into account people"s individual variations in genes, environment and lifestyle. Metabolizes about 25% of all drugs on the market. Nomenclature for polymorphisms are denoted by * . Can have multiple polymorphism with 1 * A person"s highest functioning cyp2d6 allele predicts their cyp2d6 phenotype. Patients with different metabolization have very different dose requirements. Nortriptyline is an antidepressant drug metabolized by cyp2d6. Patients with 0-1 functional cyp2d6 alleles will have much higher exposure to the drug than normal people. Multiple copies of cyp2d6 (duplication) is relatively rare in caucasians, but is fairly high in frequency in some east african populations. Need greater dose to get the same therapeutic effect. Drug company tests a population and choose a dose that most people receive therapeutical effect (with low side effects) and call it a day. After birth mother was prescribed a combination tablet containing 30 mg of codeine and.

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