Pharmacogenomics- Vet view

Question 1

Drug response

Answer 1

-same drug at same does does not always give same result
*toxicity, safety, success vs failure

Question 2

Why isn’t response uniform?

Answer 2

differences in pharmacokinetics or pharmacodynamics
*between patients OR within same patient

Question 3

Interindividual variability

Answer 3

Ex. Warfarin- prolong prothrombin/clotting times
-different people require different doses of warfarin to get the same effects

Question 4

Pharmacogenomics

Answer 4

-The influence of genetic variation within a population on drug therapy

Question 5

What do genetic differences alter?

Answer 5

1. Pharmacokinetics- time course of the drug in the body
2. Pharmacodynamics- how the drug works in the body (receptors)

Question 6

Adrenergic receptor variation

Answer 6

-alpha and beta receptors for drugs with mutations will respond differently (decreased activity or increased expression/activity)

Question 7

Pharmacokinetics and pharmacogenetics

Answer 7

ADME can be effected by genetics.
*altered enzymes

Question 8

Carvedilol drug study

Answer 8

-Given to 8 dogs. Most dogs absorbed very little. Three of the dogs heavily absorbed drug (one early, one late, one medium absorption)

-Leads to question: What dose should you give to dogs?
**most drugs have a very large therapeutic and safety window so it wouldn’t matter, but that is not the case for all dogs

Question 9

Multidrug resistance (mdr or ABCB1 gene) study

Answer 9

ABCB1 gene- protein codes for P-glycoprotein (P-gp)

Study: knockout mice for ABCB1. Mice got mites. When given ivomectin, mice died.

Question 10

White feet don’t treat

Answer 10

Collie dogs

Often have a deletion mutation of mdr (ABCB1) gene resulting in ivermectin-sensitive collies.

Question 11

Deletion mutation in ABCB1 gene

Answer 11

-4 base pair deletion mutation produced a frame shift, generating premature stop codon
=leads to truncated, non-functional P-gp

CALLED ABCB1-1delta

Question 12

Homozygous vs heterozygote gene mutation of ABCB1

Answer 12

Homozygote: have adverse effects to normally safe ivermectin

Heterozygote: one mutant, one wild type= may show toxicity at increased ivermectin doses

Question 13

Where can P-glycoprotein be found?

Answer 13

-intestinal epithelial cells
-brain capillary endothelial cells (BBB)
-biliary canaliculus cells
-renal proximal tubule cells
-placenta and testes

Question 14

P glycoprotein function

Answer 14

Actively transport chemicals from inside the cell to outside the cell
**because active transport can function against extreme concentration gradients

Question 15

Why did P-glycoprotein evolve?

Answer 15

Evolved as a protective mechanism to decrease body’s exposure to toxic xenobiotics

Question 16

What sorts of drugs does P-glycoprotein play a role in?

Answer 16

• Anticancer drugs
  -anti-infective drugs
  -parasiticides
  -opioids
  -immunomodulators
  -cardiac drugs

Question 17

P-glycoproteins impact on drug absorption

Answer 17

-P-gp is on intestinal epithelial apical membrane, so it can reduce the oral bioavailability of substrate drugs
>when gene deletion of ABC-B1 is present, can lead to an increased oral bioavailability because CYP 3A enzymes are still present and will be bringing drugs inside

Question 18

Cyclosporine

Answer 18

Atopica- expensive and not absorbed well

Question 19

P-gp substrate and inhibitor drugs given concurrently

Answer 19

Ketaconazole- another substrate for P-gp and CYP enzymes. Will inhibit P-gp efflux activity and CYP 3A metabolic activity
=Leads to chance of increase in cyclosporin absorption

**dangerous as toxicity can occur

Question 20

P-gp and drug excretion

Answer 20

-P-gp is expressed on renal tubular cells and bile canaliculus cells, and transports drugs into the urine/bile enhancing their excretion

-If P-gp affected by mutation, will decreased renal or biliary excretion and can increase drug exposure (longer elimination half-life)

Question 21

ABCB1 and vincristine toxicity

Answer 21

Homozygous and heterozygous mutant for ABCB1 gene
- both groups had some form of thrombocytopenia/neutropenia/toxicity BUT more serious for homozygous
-also saw some wild type border collies that also had some mild neutropenia

Question 22

P-gp and drug distribution

Answer 22

P-gp is normally expressed on brain capillary endothelial cells and function as part of the BBB by pumping drugs out of CNS
**dogs with ABCB1 mutation have increased brain concentrations of drugs

Question 23

Testing for ABCB1 gene

Answer 23

-cheek or blood sample. Send to pharmacology lab $70
-1-2 weeks
-looks for gene mutation by PCR analysis

Question 24

CYP polymorphisms

Answer 24

-there is variation in cytochrome enzyme expression or function which has major impact on drug metabolism and clearance
**CYP tests not available for individuals yet

Question 25

Polymorphisms in CYP2B11

Answer 25

may account for slow propofol metabolism and prolonged anesthesia in Greyhounds

Question 26

Testing cats with toxicity history from P-gp substrate drugs

Answer 26

-Looked at 8 cats, only 1 had ABCB1 gene deletion. Others had multiple point mutations throughout the ABCB1 gene

Question 27

Cats and ABCG2 gene

Answer 27

-ABCG2 encodes for transporter and when mutations are present, we see a decrease in transported function
>may possibly be linked with Fluoroquinolone-induced retinal toxicity (accumulation in retina), and Acetaminophen induced toxicity (low biliary clearance of acetaminophen)