9 – Pharmacogenomics Flashcards
Why isn’t the response of a drug therapy always uniform?
- Differences in PK or PD
o Between patients
o Within same patient - NOT variability in drug products
Example: interindividual variability with warfarin
- Anti-coagulation=prolong prothrombin times
- Don’t want to be TOO LONG or TOO short
- *different people require different doses to get a desired effect
Pharmacogenomics
- Influence of GENETIC VARIATION within a population on drug therapy
o May alter PK (ADME) and PD - *we do NOT know what ‘type’ of animal we will be treating
- Ex. time course or receptors
PD effects: adrenergic receptor mutations
- Won’t respond the same way when the drug tries to bind to it
- Down regulation or up regulation
Multidrug resistance (mdr) gene: ABCB1 gene
- Codes for P-glycoprotein (P-gp)=ABCB1 protein
o Membrane transporter pump (apical membrane) - ‘knockout’ mice (gene deleted): normal until got mites
o Drug: ivermectin
o MICE dropped dead - *collie bred dogs
White feet, don’t treat
- Collie breed dogs (white feet)
- Do NOT treat with Ivermectin=susceptible to ivermectin toxicity
Why are collies ivermectin sensitive?
- Deletion mutation in mdr (ABCB1) gene = produced a frame shift (premature stop codon) = get a non-functional P-gp
Homozygous gene mutation of mdr gene
- Adverse effects to normally safe doses of ivermectin
Heterozygote gene mutation of mdr gene
- May show toxicity at increased ivermectin doses
P-glycoprotein expressed in many cell types
- Intestinal epithelial cells
- Brain capillary (BBB) endothelial cells
- Biliary canaliculus cells
- Renal proximal tubule cells
- Placenta and testes
What is the function of P-gp?
- Actively transports chemicals from INSIDE the cell to OUTSIDE the cell
o *active=can function against EXTREME concentration gradients
P-gp evolved as a
- Protective mechanism to decrease body’s exposure to toxic xenobiotics
- “the bouncer”
- *works on many drug classes (why first called ‘mdr gene’)
P-gp and oral drug absorption
- Expressed on intestinal epithelial apical membranes=can REDUCE oral bioavailability of substrate drugs
- *if have ABCB1 gene deletion=INCREASED oral bioavailability to many drugs
Drugs that are P-gp substrates may also be substrates for
- CYP 3A enzymes
Absorption ‘steps’
- Need to get absorbed (avoid P-gp)
- Then make it through the liver (avoid CYP3A enzymes)
- Enter capillary portal vein
What can be used to increase oral bioavailability?
- Cyclosporine
- Ketoconazole: another substrate for P-gp and CYP enzymes
*Inhibits P-gp efflux activity and CYP3A metabolic activity - *need to be very careful as toxicity can occur
P-gp and drug excretion
- Transports drugs into urine/bile=enhancing excretion
- Decreases renal or biliary excretion (ex. reduced P-gp) can INCREASE drug exposure (=AUC) and elimination half life
Vincristine toxicity and ABCB1 genetics
- Thrombocytopenia=more in those with a mutated gene
- Neutropenia grade=high in mutant dogs
- *3 WT/WT with neutropenia were border collies
o ABCB1 was normal, possible a CYP gene mutation?
P-gp and brain capillary endothelial cells
- Function as part of BBB by pumping drugs out of CNS
P-gp and drug distribution: ABCB1 gene deletion
- *increased brain concentrations of many drugs
- Ex. ivermectin, moxidectin, corticosteroids, Ioperamide (AVERMECTIC TOXICITY)
Avermectin toxicity
- Ivermectin and related drugs
- Not a problem when part of heartworm preventative dose (concentration is so little)
Breed incidence
- Can try and use to know how it may be to use the drug
Get a dog and want to know if it has P-gp mutation
- TEST before treating
- Check epithelial OR blood sample
- 1-2 week turn around
What about CYP polymorphisms?
- Variances in enzymes expression or function=major impact on drug metabolism and clearance
- May account for prolonged anesthesia in Greyhounds
- *no pharmacogenomic test available yet for individual dogs
Cat pharmacogenomics?
- Only 1/8 of cats had similar ABCB1 gene deletion as in dogs
- *but affected cats, had multiple other point mutations throughout the ABCB1 gene
ABCG2 transporter genes
- Encode for another transporter
- Expressed in similar tissues as P-gp (ex. breast cancer RP (BCRP))
Humans with ABCG2 polymorphisms have
- Decreased transporter activity=increase exposure to substrate drugs
Feline ABCG2 transporter genes
- Several AA differences at conserved sites
- *lead to decreased transporter function
- **CONSISTENT in all cats (NOT just a sub-population)
- Ex. fluroquinolone-induced retinal toxicity OR acetaminophen-induced toxicity?
