Pharmacogenetics

Question 1

what can genetic variability cause in respect to drugs?

Answer 1

adverse drug reactions: excessive drug concentrations
treatment failures: inadequate drug concentrations

Question 2

what can be a single nucleotide polymorphism (SNP)?

Answer 2

amino acid change
premature stop codon
mRNA splicing error
amount of mRNA transcription

Question 3

what sites affect drug disposition?

Answer 3

drug transporters
drug metabolizing enzymes

Question 4

what are some causes of variability between species?

Answer 4

low feline glucuronidation capacity
dogs lack acetylation enzymes
deficient pig sulfation

Question 5

what is the most famous drug transporter?

Answer 5

P-glycoprotein

Question 6

where is P-glycoprotein located?

Answer 6

blood-brain barrier
intestinal and bronchial epithelium
renal tubules and liver canaliculi

Question 7

what gene mutation is important in P-glycoprotein?

Answer 7

multiple drug resistance gene ABCB1 (MDR1) mutation

Question 8

what is the role of P-glycoprotein?

Answer 8

limit oral absorption
restricts entry into CNS
facilitates renal and liver excretion

Question 9

what are two analgesic/tranquilizer P-glycoprotein substrates?

Answer 9

butorphanol
acepromazine

Question 10

what are some non-analgesic/tranquilizer P-glycoprotein substrates?

Answer 10

ivermectin
emodepside
anticancer agents (vincristine and doxorubicin)
loperamide (imodium AD)
anything that impacts action is as well: predisone and spinosad

Question 11

what percent of cats has feline ABCB1 nonsense mutation?

Answer 11

5% of those studied
phenotype is same as ABCB1-1delta mutation in dogs

Question 12

what is the clinical significance of the ABCB1-1delta mutation?

Answer 12

excessive neurotoxicity
excessive drug effect causing sedation
impaired drug excretion leading to toxicity

Question 13

are morphine, buprenorphine, and fentanyl known to cause excessive sedation in susceptible dogs?

Answer 13

no reports
butorphanol dosing recommendations: 3/4 dose for heterozygotes and 1/2 for homozygotes

Question 14

what can you use to reverse opioids?

Answer 14

nalaxone

Question 15

true/false: ivermectin is safe for dogs with ABCB1-1delta at the normal heartworm dose

Answer 15

true
only when overdoses

Question 16

what drug inhibits P-glycoprotein and can therefore make normal dogs behave like mutant dogs pharmacologically?

Answer 16

spinosad
also is a substrate

Question 17

what breeds of dogs have a high prevalence of ABCB1-1delta?

Answer 17

australian shepherds (also minis)
collie (not so much border collies)
longhaired whippet

Question 18

what are the breeding recommendations for reducing the amount of dogs with ABCB1-1delta?

Answer 18

avoid breeding homozygous ABCB1-1delta dogs
ideally breed only wildtype ABCB1 dogs
ensure one parent is unaffected at least

Question 19

how does prednisone affect P-glycoprotein?

Answer 19

upregulates it
more than 7 days of prednisone will decrease impact of chemotherapy

Question 20

is there variation by species with the cytochrome P450 enzyme system?

Answer 20

yes- significant

Question 21

where is the cytochrome P450 enzyme system?

Answer 21

most important is liver

Question 22

what does the cytochrome P450 enzyme system do?

Answer 22

inactivates most drugs

Question 23

what is special about greyhounds?

Answer 23

reduced activity of 2B11 in the liver
prolonged action of thiobarbiturates