Pharmacogenomics

Question 1

what is variable in drug therapy?

Answer 1

same drug doesnt always produce the same effect in diff patients; there can be treatment success or failure; there can be presence or absence of adverse effects

Question 2

why arent drug responses always uniform?

Answer 2

there are differences in PK & PD; PK-PD differences BTWN patients & W/IN the same patient

Question 3

What is pharmacogenomics?

Answer 3

influence of genetic variation w/in a population on drug therapy

Question 4

What can genetic differences alter?

Answer 4

• PK (time course of drug in body)
• PD (how drug works in body)

Question 5

Ex of pharmacogenetic PD effects?

Answer 5

adrenergic receptor mutations

Question 6

How does pharmacogenetics influence PK effects?

Answer 6

PK is comprised of 4 processes (ADME) & genetics can influence all of them!

Question 7

What is ABCB1?

Answer 7

multi-drug resistance gene - mdr (now called ABCB1 gene) codes for P-glycoprotein (P-gp) (now called ABCB1 prot) which is a mb transporter pump
knockout mice for ABCB1 were normal until given dose of ivermectin

Question 8

What dog breed has a deletion mutation of ABCB1 (mdr) & is therefore incredibly sensitive to ivermectin?

Answer 8

collie breeds

Question 9

Describe the deletion mutation of mdr (ABCB1) gene in ivermectin-sensitive collies:

Answer 9

• 4 base-pr deletion mutation produces frame shift, generating premature stop codon
• results in truncated, non-fxnal P-gp
• mutation is referred to as ABCB1-1(triangle)

Question 10

Clinical observations of deletion mutation of mdr (ABCB1) gene in ivermectin-sensitive collies:

Answer 10

• dogs w/ homozygous gene mutation have adverse effects to normally safe doses of ivermectin
• heterozygote dogs (1 mutant, 1 wild-type) may show toxicity @ increased ivermectin doses

Question 11

Where is P-gp expressed?

Answer 11

in many cell types (Ex: intestinal epithelial, BBB endothelial, biliary canaliculus, renal proximal tubule, placenta, & testicular cells)

Question 12

what is fxn of P-gp?

Answer 12

to actively transport chemicals from INSIDE the cell to OUTSIDE the cell (b/c active transport, it can fxn against extreme concentration gradients)

Question 13

Why did P-gp evolve?

Answer 13

evolved as protective mech to decrease body’s exposure to toxic xenobiotics; “the bouncer”

Question 14

what does P-gp confer resistance to?

Answer 14

1. anticancer drugs (doxorubicin)
2. anti-infective drugs (ketoconazole)
3. parasiticides (avermectins)
4. opioids (morphine)
5. immunomodulators (corticosteroids)
6. cardiac drugs (digoxin)

Question 15

Why did ABCB1 used to be called MDR gene?

Answer 15

b/c it confers resistance to many chemotherapy & antimicrobial drugs

Question 16

How is P-gp related to oral drug absorption?

Answer 16

P-gp can REDUCE oral bioavailability of substrate drugs; P-gp is expressed on intestinal epithelial apical mb so the drug stays in lumen; drugs that are substrates for P-gp may also be substrates for CYP 3A enzymes (so in order to get in drug would need to avoid both of these enzymes)
dogs w/ ABC-B1 gene deletion have INCREASED oral bioavailability to many drugs

Question 17

4 things that may happen to P-gp & CYP 3A substrate drug in gut lumen:

Answer 17

1. runs into P-gp (not absorbed)
2. runs into CYP 3A enzymes & gets metabolized (sometimes these metabolites are helpful & sometimes harmful)
3. gets in & is absorbed
4. could just get excreted

Question 18

How do you increase oral availability of cyclosporine?

Answer 18

use ketoconazole which is another substrate for P-gp & CYP enzymes that will inhibit P-gp efflux activity & CYP 3A metabolic activity; concurrent use of P-gp substrate & inhibitor drugs must be done v carefully as toxicity can occur

Question 19

How is P-gp related to drug EXCRETION?

Answer 19

• P-gp is expressed on renal tubular cells & bile canaliculus cells
• it transports drugs into urine or bile, enhancing their excretion
• decreased renal or biliary excretion can increase drug exposure (longer elimination half-life)

Question 20

How is P-gp related to drug DISTRIBUTION?

Answer 20

• P-gp is normally expressed on brain capillary endothelial cells & fxns as part of BBB by pumping drugs out of CNS

Question 21

How dose the ABCB1 gene deletion affect drug distribution?

Answer 21

• dogs with this mutation have increased brain concentrations of many drugs (ex: ivermectin, moxidectin, loperamide, corticosteroids)

Question 22

What is avermectin toxicity?

Answer 22

-Toxicity from Ivermectin, selamectin, moxidectin, etc. in dogs w/ ABCB1 gene deletion
- heartworm preventative dose is safe even in mut/mut dogs

Question 23

How do you know if your patient carries ABCB1-1(triangle) mutant gene?

Answer 23

• in NA, WSU vet pharmacology lab performs ABCB1 genetic testing (uses PCR analysis)
• requires cheek epithelial OR blood sample

Question 24

How do CYP polymorphisms affect drugs in dogs?

Answer 24

• variance in cytochrome enzyme expression or fxn has mjr impact on drug metabolism & clearance
• polymorphisms in CYP2B11 in dogs may account for slow propofol metabolism & prolonged anesthesia in Greyhounds
• NO CYP PHARMACOGENOMIC TEST AVAILABLE (YET) FOR INDIVIDUAL DOGS

Question 25

ABCB1 gene in Fe?

Answer 25

• 8 Fe w/ hx of toxicity from P-gp substrate drugs were ABCB1 genotyped
• only 1/8 Fe had similar ABCB1-1 (triangle) gene deletion as in Ca (2 bp)
• BUT affected Fe had multiple other pt mutations throughout ABCB1 gene

Question 26

ABCG2 transporter in Fe?

Answer 26

• encode for another transporter
• expressed in similar tissues as P-gp
• humans w/ ABCG2 polymorphisms have decreased transporter activity and therefore increased exposure to substrate drugs
• several AA differences @ conserved sites compared to other mammalian spp
• differences in Fe ABCG2 lead to decreased transporter fxn
• Fe ABCG2 AA sequence appears CONSISTENT in all Fe, not just a sub-population

Question 27

Which adverse events in Fe may be due to ABCG2 defects?

Answer 27

• fluoroquinolone-induced retinal toxicity where FQ accumulates in retina due to decreased ABCG2 efflux
• acetaminophen-induced toxicity from decreased biliary clearance of acetaminophen due to decreased ABCG2 efflux & production of more toxic metabolites by other pathways