Chapter 5: Pharmacogenomics and Drug Transporters Flashcards
Test 1
Define pharmacogenomics and its importance in personalized medicine
The study of how an individual’s genetic makeup affects their response to drugs.
It is important for personalized medicine because it allows for predicting drug efficacy and toxicity based on a patient’s genetic profile.
What does idiosyncratic mean?
Unusual drug response
Name and describe three drugs that may require dosage adjustments in specific genetic populations, the enzyme or mutation responsible, and the type of testing done to determine susceptible populations.
- Herceptin which blocks the Her2 receptor on cancer cells
-Her2
-Required Biopsy to see if cancer is HER2-positive (over expressing Her2) - Warfarin which is metabolized by CYP2C9
-CYP2C9
-Recommended genetic testing for dose adjustments based on CYP2C9 genetic variants - Codeine - Dosage adjustments based on CYP2D6 genetic variants, which affect conversion of codeine to the active metabolite morphine.
required prior to 6MP administration
How many gene bases do we have?
3.2 billion base PAIRS
6.4 billion bases with both strands
_____% of DNA codes for protein
1-2%
_____ % of us have the same DNA
99.9
How many genes do we have?
30,000
How many Single base pairs variants (Single nucleotide polymorphism or SNP) do we have?
More than 1 million
What is an locus/loci?
Exact location on a chromosome
What are alleles?
An alternate form of a gene at the same loci
What is a silent mutation?
The different allele doesnt change the amino acid and is not even detectable unless theres a DNA scan.
What does PM stand for?
Poor Metabolizer
Prodrug + poor metabolizer =
Drug cannot be activated that well. Wont reach its full efficacy
Accumulation of prodrug because not being metabolized (Not being activated nor excreted)
Active drug + poor metabolizer =
High efficacy
Stays in the system longer
Not being metabolized fast therefore not being inactivated fast and not excreting fast (stays in system longer)
May need lower dose and/or longer intervals so wont have toxic levels
Prodrug + ultarapid metabolizer =
Works fast, high efficacy
Active drug + ultrarapid. metabolizer =
Inactivated quick
Cant even reach its full efficacy because its metabolized and inactivated/excreted so quick
Needs greater dose or slow release
CYP2D6
Absent in 7% of Caucasians
Hyperactive in 30% of East Africans
Catalyzes metabolism: Betablockers, Class 1C antiarrhythimcs, Analgesics, Various antidepressants/physchotics
5HT3 inhibitor
What activates Codeine?
CYP2D6
What inactivates Codeine
CYP3A4 to Norcodeine
What is warfarin metabolized by?
CYP2C9
Describe Warfarin
Metabolized by CYP2C9
Racemic mixture of R- and S- Warfarin
S- warfarin 7-10x more potent
What happens if you carry a variant allele of CYP2C9 while taking warfarin?
Reduced metabolism of warfarin leading to higher concentrations of warfarin therefore higher risk of bleeding.
What causes breast cancer?
Overproducing Estrogen and Progesterone receptors
What type of treatment is included in breast cancer?
Estrogen deprivation
HER2+ cancers respond to what drug?
Herceptin
What is required before starting Herceptin?
Biopsy with genetic testing to determine is the tumor is overproducing th HER2 gene
Describe the role of drug transporters in the cell
Primary function is to transport endogenous substances
Drug transporters play a role in moving or preventing drugs and other substances across cell membranes, facilitating both influx and efflux.
Active Transport Requires____
ATP
Facilitated diffusion requires a ______
Concentration Gradient
What are the special carriers?
Active transport and facilitated diffusion
What are 4 specialized barriers?
Blood-brain
Blood-placenta
Blood-testes
Blood-ovarian
What does xenobiotic mean?
Something thats been introduced into the body
Define the role of drug efflux transporters
Drug efflux transporters, such as the ATP-binding cassette (ABC) transporters, actively pump drugs out of cells, reducing intracellular drug concentrations.
This can cause drug resistance.
70% of genes are _______
Transporters
What are 3 types of passive transporters?
Coupled
Exchanger
Passive
What is a coupled transporter?
It takes 2 things simultaneously through a “sim porter” or coupled transporter
Ex) SGLT
Passive transport _____ require ATP
does not
What is an Exchanger transporter?
1 thing goes out and another goes in. Important in the heart.
Ex) NCX
What is the most important active transporter?
Na/K ATPase
List the most important ABC transporters and differences in their drug affinity
***ABCB1 (broadest substrate specificity including antineoplastics, HIV protease inhibitors antibiotics, antidepressants, antiepileptics, and opioids). They also have a wide distribution in the body (GI, kidney, liver, testes) and are critical to the maintenance of the blood-brain barrier (BBB)
- Remember quinidine, cyclosporine A, and Ritonavir are competitive inhibitors to ABCB1
- Digoxin is transported by ABCB1 and, if inhibited, ABCB1 won’t remove as much resulting in toxic plasma levels.
- Loperamide typically has no CNS effects but if ABCB1 is inhibited, systemic absorption can occur resulting in CNS effects like respiratory suppression***
- ABCC - Largest class; ubiquitous; antineoplastics drug
- ABCG2 is known as the breast cancer resistance protein (BCRP) (antineoplastics, toxins, food-born carcinogens)
- Also, an efflux transporter of folate
ABC transporter require_____
ATP
ATP binding cassette transporters
Describe an ABC transporter?
Transmembrane spanning domains and NBD (Nucleotide binding domains) intracellularlly.
The ATP binds at The C-terminus NBD and then the drug can be pumped out or in to the cell (this depends on the location and orientation of the receptor)
What separates the gut from the blood?
The basal membrane (closest to blood) and the apical surface (closest to gut)
Analyze the anatomic differences between drug transporters in different organs and their overall effects
Drug transporters are differentially expressed in organs like the intestine, liver, kidney, and blood-brain barrier. This affects drug absorption, distribution, metabolism, and elimination
List the components of the intact blood-brain barrier
-The intact blood-brain barrier consists of the vascular endothelium with tight junctions, astrocytes, and podocytes; which together restrict the entry of most drugs into the brain. It has many efflux transporters so even when a drug is allowed in, it may be immediately pumped back out before its effects are seen
-Tight junctions and adherens junction complexes
Where does the ABCB1 mostly sit?
On the Apical surface
Why cant some drugs be taken orally?
Some drugs if taken orally will just get pumped back out by an efflux transporter
Where are drugs entered and filtered into the kidney?
The Glomerulus
Where are most of the transporters on the BBB?
The vascular epithelium
Delineate the pathway of Tylenol in the gut before and after biotransformation
Describe the transporters for the Blood-CSF barrier
On the Pia matter and ependymal cells
Less efflux
Not effective for antineoplastics
