Pharmacology 3620 Lecture Notes - Lecture 9: Vitamin K Epoxide Reductase, Cyp2D6, Pharmacogenetics
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
find more resources at oneclass.com
find more resources at oneclass.com
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
find more resources at oneclass.com
find more resources at oneclass.com
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.