Pharmacogenomics Flashcards
what is variable in drug therapy?
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
why arent drug responses always uniform?
there are differences in PK & PD; PK-PD differences BTWN patients & W/IN the same patient
What is pharmacogenomics?
influence of genetic variation w/in a population on drug therapy
What can genetic differences alter?
- PK (time course of drug in body)
- PD (how drug works in body)
Ex of pharmacogenetic PD effects?
adrenergic receptor mutations
How does pharmacogenetics influence PK effects?
PK is comprised of 4 processes (ADME) & genetics can influence all of them!
What is ABCB1?
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
What dog breed has a deletion mutation of ABCB1 (mdr) & is therefore incredibly sensitive to ivermectin?
collie breeds
Describe the deletion mutation of mdr (ABCB1) gene in ivermectin-sensitive collies:
- 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)
Clinical observations of deletion mutation of mdr (ABCB1) gene in ivermectin-sensitive collies:
- 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
Where is P-gp expressed?
in many cell types (Ex: intestinal epithelial, BBB endothelial, biliary canaliculus, renal proximal tubule, placenta, & testicular cells)
what is fxn of P-gp?
to actively transport chemicals from INSIDE the cell to OUTSIDE the cell (b/c active transport, it can fxn against extreme concentration gradients)
Why did P-gp evolve?
evolved as protective mech to decrease body’s exposure to toxic xenobiotics; “the bouncer”
what does P-gp confer resistance to?
- anticancer drugs (doxorubicin)
- anti-infective drugs (ketoconazole)
- parasiticides (avermectins)
- opioids (morphine)
- immunomodulators (corticosteroids)
- cardiac drugs (digoxin)
Why did ABCB1 used to be called MDR gene?
b/c it confers resistance to many chemotherapy & antimicrobial drugs
How is P-gp related to oral drug absorption?
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
4 things that may happen to P-gp & CYP 3A substrate drug in gut lumen:
- runs into P-gp (not absorbed)
- runs into CYP 3A enzymes & gets metabolized (sometimes these metabolites are helpful & sometimes harmful)
- gets in & is absorbed
- could just get excreted
How do you increase oral availability of cyclosporine?
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
How is P-gp related to drug EXCRETION?
- 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)
How is P-gp related to drug DISTRIBUTION?
- P-gp is normally expressed on brain capillary endothelial cells & fxns as part of BBB by pumping drugs out of CNS
How dose the ABCB1 gene deletion affect drug distribution?
- dogs with this mutation have increased brain concentrations of many drugs (ex: ivermectin, moxidectin, loperamide, corticosteroids)
What is avermectin toxicity?
-Toxicity from Ivermectin, selamectin, moxidectin, etc. in dogs w/ ABCB1 gene deletion
- heartworm preventative dose is safe even in mut/mut dogs
How do you know if your patient carries ABCB1-1(triangle) mutant gene?
- in NA, WSU vet pharmacology lab performs ABCB1 genetic testing (uses PCR analysis)
- requires cheek epithelial OR blood sample
How do CYP polymorphisms affect drugs in dogs?
- 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
ABCB1 gene in Fe?
- 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
ABCG2 transporter in Fe?
- 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
Which adverse events in Fe may be due to ABCG2 defects?
- 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
