Exam 1 - Ch. 5 review Flashcards
Define pharmacogenomics and its importance in personalized medicine.
Helps predict, explain and treat patients specific to their genetic profile. It allows us to tailor doses and treatment plans based on genetic variants for better outcomes.
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, warfarin, 6-mercaptopurine
all would need genetic testing.
6-mercaptopurine has genetic variation in a gene called TPMT. Some need less of the drug, and some need even less or else it could be fatal.
Herceptin requires a simple blood test
Warfarin is metabolized by CYP2C9, and those with CYP2C9*2 or *3 have reduced metabolism. leads to toxic amounts.
Describe the role of drug transporters in the cell membrane
primary: Transport endogenous substances across membrane, mostly passive transport.
Can have a role in drug absorption and can facilitate or prevent drug entry into the body.
What % of genes are transporters
7%
Majority of transporters have a high:
substrate specificity, such as Na, glucose, amino acids.
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 (antineoplastics)
ABCG2 is known as the breast cancer resistance protein (BCRP) (antineoplastics, toxins, food-born carcinogens)
Also, an efflux transporter of folate
Define the role of drug efflux transporters
Discovered by oncologists because cancer cells were pumping drugs out of their cells. Bind to drugs and transports them into or out of the cell. They increase in numbers when they see more drugs, it’s a cell survival mechanism.
Do efflux transporters require ATP?
yes
What does ABC transporters stand for?
ATP-binding Cassette Transporters
How do ABCs sit on membrane?
Transmembrane spanding domains, NBD on inside.
where does ATP bind on a ABC?
To the NBD
ABCA1
Cholesterol, can pump in or out
ABCB1
Broadest substrate specificity: antineoplastcis, HIV protease inhbitors, antibx, antidepressants, antiepileptics, opioids.
Some cancers increases ABCB1
GI, liver, kidney, testes.
CRITICAL FOR BLOOD BRAIN BARRIER
what does ABCB1 do in BBB
Orientated in apical surface to pump drugs out that somehow got into lining
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
- ABC transporters
- Vascular epithelium (tight!!!)
- Other cells such as astrocyte and podocytes.
Delineate the pathway of Tylenol in the gut before and after biotransformation
Acetaminophen (Tylenol) is absorbed in the gut and undergoes first-pass metabolism in the liver, where some is conjugated with glucuronic acid (glucuronidation). The glucuronide conjugate is then transported back into the intestine via bile and, instead of being reabsorbed into the bloodstream by ABCG2 transporters, ABCC transporters recognize it as a waste product and pump it back into the intestines to be eliminated in the feces.
Blood volumes in body: whole blood and plasma
Whole blood: 5.6L/70kg
Plasma: 2.8L/70kg
Characteristics of ABCs (what he drew)
You’ve got the gut, transporters on Apical side of epithelial cells here facing gut, then other side of epithelial cells you got the basal membrane side, which has transporters that allow it into blood stream.
Drug interactions for ABCB1
Cyclosporine, quinidine, ritonavir all inhibits ABCB1
e.g. digoxin interacts with one of these above drugs and increases toxicity
ABCC
Largest class, ubiquitous, but not as many drugs as ABCB. Antineoplastic
ABCG2
Breast cancer resistant protein (BRCP)
Antineoplastics, toxins, food-borne carcinogens, found in GI-tract.
Non-ABC drug efflux transporters
no ABC, largely passive.
SLC21
type of non-abc
-OATPs
-Some for influx and some efflux, depending on orientation in membrane
Most drugs in relation to BBB do not
cross
Majority of arrows are pointing in or out of liver?
Into.
Majority of arrows are pointing in or out of kidney tubule?
Into
8 things that can cross BBB
small lipophilic molecules, O2, CO2, ethanol, nicotine, insulin, glucose, albumin
Tylenol animation
Tylenol goes into gut, across bloodstream, to first-pass effect (glucuronidation resulting in glucuronide), put into bile, bile dumps into intestine, the ABC transporters in gi tract recognize the glucuronidation and pump it right back out into intestines to be excreted.
