Week 5: Pharmacogenetics and Routes of Drug Flashcards
Precision Medicine
An emerging approach for disease prevention and treatment that takes into account people’s individual variations in genes, environment and lifestyle.
Tailor therapies to the individual person
Pharmacogenetic Examples
- Phase I Drug Metabolizing Enzymes
CYP2D6
CYP2C9 - Phase II Drug Metabolizing Enzymes
TPMT
UGTIAI - Drug Transport Proteins
OATPIBI - Drug Targets
β1 adrenergic receptor
Vitamin K epoxide reductase complex 1
CYP2D6
CYP2D6 metabolizes approximately 25% of all drugs on the market.
- Variable response was originally described by two independent laboratories at the same time.
- CYP2D6 is one of the prototypical examples in pharmacogenetics as there exists SNPs, ins/dels and copy number variations.
- Most others only has SNPs
- All of the variations can impact drug response
- There are over 90 known allelic variants in CYP2D6.
Metabolizes Nortriptyline
Nomenclature of CYP2D6
Polymorphisms in drug metabolizing enzymes like CYP2D6 are often referred to by the “*” nomenclature.
- For example, CYP2D61 represents the wild-type sequence whereas CYP2D63 has an A2367del (deletion of a nucleotide at this position).
- The star nomenclature often represents more than one polymorphism.
- For example, CYP2D6*4 has multiple polymorphisms
Phenotype of CYP2D6
A person’s highest functioning CYP2D6 allele predicts their CYP2D6 phenotype
Debrisoquine : 4-OH Debrisoquine urinary ratio
Ultrarapid Metabolizers
Low ratio means that they are metabolizing debrisoquine really fast
- Either you have 3 copies of the gene or 2 of the fully functioning allele
- Need a much higher dose for the drug (Nortriptyline) to take effect (therapeutic response)
Extensive Metabolizers
High ratio means that they are metabolizing debrisoquine slowly
-Either you have 2 of the fully functional alleles or 1 fully functional, 1 less functional (or non-functional) allele
Intermediate Metabolizers
High ratio means they are metabolizing debrisoquine slowly
-Either you have 1 decreased function, 1 null function allele or 2 decreased function alleles
Poor Metabolizers
High ratio means that they are metabolizing debrisoquine really slowly
- Either you have 2 non-functional alleles or 1 non functional, one missing (gene deletion) allele
- Need a much lower dose of the drug (Nortriptyline) to take effect (therapeutic response) or overdose
Codeine
Codeine is an analgesic that is used to treat minor to moderate pain.
- Codeine is a prodrug (its metabolite has pharmacological activity).
- Codeine is metabolized by CYP2D6 to morphine (higher pharmacological activity than codeine)
CYP2C9
CYP2C9 is highly expressed in the liver.
- It is the second most abundant CYP enzyme in the liver.
- It metabolizes 15 - 20% of all drugs including phenytoin (for seizures), warfarin (anticoagulant), tolbutamide (for TII diabetes).
- There are two common polymorphisms in CYP2C9: CYP2C92 and CYP2C93.
- Both polymorphisms result in reduced enzymatic activity.
Phenytoin
Phenytoin is an anti seizure medication.
It’s primarily metabolized by CYP2C9 (~83%).
Minimally metabolized by CYP2C19
Genotyping revealed that the patient did not have either the CYP2C92 or CYP2C93 polymorphisms (usually result in reduced function).
Analysis of serum phenytoin concentrations over the 40 days revealed a markedly increased half life (~13 days).
The CYP2C9 gene was sequenced and a novel polymorphism identified 818delA.
This polymorphism results in the production of a null allele.
The allele frequency is 0.6% in African Americans
Pharmacogenetics of THC
The active component in marijuana is THC.
THC is metabolized by CYP2C9.
Polymorphisms impact exposure to THC.
Thiopurine Methyltransferase
TPMT is a phase II drug metabolizing enzyme.
Catalyzes the transfer of a methyl group onto thiopurine drugs such as azathioprine and 6- mercaptopurine.
The methylated metabolites are non-toxic.
Azathioprine and 6-mercaptopurine are used to treat certain types of cancer and inflammatory bowel disease.
These drugs have a low therapeutic index and may cause life threatening myelosuppression.
You must be genetically tested
TPMT has several polymorphisms that affect its enzyme activity.
TPMT was the first example of a drug to have pharmacogenetic information provided in the drug labelling.
We want the active form to treat cancers/bowel disease (toxic but active)
If someone has a polymorphism in TPMT that affects their TPMT activity, we will get much more of the toxic active form → bone marrow suppression
Make sure the patient has TPMT activity before giving the drug
The TPMT3A polymorphisms are common with an allele frequency of ~ 5%.
Approximately 1 in 300 people have two copies of the TPMT3A allele which has no measurable enzyme function.
The protein formed in subjects with the *3 allele undergoes accelerated degradation.
In patients with two copies of the *3 allele an alternate treatment should be considered.
If an alternate treatment is not possible the dose should be reduced 10-fold and administered three times per week instead of daily.
UDP Glucuronosyltransferase IAI (UGTIAI)
UGTIAI is a phase II enzyme.
Irinotican is a prodrug that is metabolized by carboxylesterase → SN38
Can cause bone marrow depression → leukopenia, or intestinal epithelium issues → diarrhea
Catalyzes the transfer of a glucuronic acid onto xenobiotics rendering them more polar so they can be excreted.
UGT1A1 glucuronidated the anti-cancer drug irinotecan making it less toxic.
The glucuronidated version is non-toxic but also will not treat the diseases, so you need SOME circulation effects (SN38)
Usually UGTIAI will prevent some of the systemic circulation effects
If we do not have UGTIAI step, you will go down the bad pathway because the SN38 is not glucuronidated
