Pharmacogenomics

Question 1

Phase I enzymes

Answer 1

CYP2D6, CYP2C19, CYP3A4 and CYP3A5, Dihydropyrimidine Dehydrogenase (DPD), CYP2C9 and VCORC1

Question 2

What family of enzymes is involved with functionalization in phase I?

Answer 2

P450 enzymes

Question 3

What family of enzymes is involved in conjugation of phase II?

Answer 3

transferases

Question 4

Functionalization

Answer 4

a functional group is added to a drug, causing it to become ionized

Question 5

conjugation

Answer 5

large polar group is added to the functional group of a drug and becomes much more polar and easy to excrete

Question 6

What is metabolism for?

Answer 6

removing foreign molecules from the body

Question 7

enzyme induction

Answer 7

enzymes can be up-regulated in response to specific foreign bodies entering the body in preparation for the next time foreign molecule enters the body

Question 8

p-glycoprotein

Answer 8

ATP-dependent drug efflux transporter (pumps drugs out of the cell) with broad substrate specificity. Causes reduced efficacy of drugs.

Question 9

How does drug-drug interaction occur through drug absorption?

Answer 9

direct interaction between drugs

altering gastric pH (such that orally administered drug is ionized and cannot enter the cell membrane).

Inhibiting P-glycoprotein, which would cause more drug accumulation in cells.

Question 10

PXR/PXR

Answer 10

nuclear receptor that senses the presence of foreign molecules and up-regulates the expression of proteins that clear these molecules from the body

Question 11

AhR cytoplasmic receptor

Answer 11

ligand-activated transcription factor that regulates cytochrome P450.

Question 12

How do drug-drug interactions occur via drug excretion?

Answer 12

increase renal blood flow and therefore increasing glomular filtration rate

inhibit active tubular secretion

alter tubular reabsorption

Question 13

What is the basis of pharmacogenomics?

Answer 13

genetic variants (SNPs, indels, CNVs) between patients leads to varied response to drugs between patients

Question 14

What happens if the pH is higher than the pKa of a weak acid drug?

Answer 14

drug is deprotonated and charged due to more basic environment, and is cleared more easily from the body

Question 15

How is renal excretion controlled?

Answer 15

via adjusting urine pH

Question 16

How are drugs excreted via the biliary tract?

Answer 16

via enterohepatic circulation: drug is brought into the liver from small intestine, made into bile salts -> gallbladder -> to gut in metabolized form -> turned back into non-metabolized form by bacteria in the gut

Question 17

How does renal excretion work?

Answer 17

blood is filtered in the glomerulus and metabolized (polar) drugs do not get reabsorbed so they remain in the urine and are flushed out of the body

Question 18

Examples of zero-order kinetics drugs

Answer 18

ethanol, phenytoin, aspirin

Question 19

First order elimination characteristics

Answer 19

elimination rate proportional to drug plasma concentration

has a half-life

Question 20

zero order elimination characteristics

Answer 20

elimination rate is constant

process is saturated (does not change with concentration changes)

Question 21

What is clearance a measure of?

Answer 21

efficiency of irreversible removal of a drug by an elimination organ

Question 22

What is the equation for half-life?

Answer 22

t1/2 = (0.7 x Vd)/CL

Question 23

What is the equation for maintenance dosing rate?

Answer 23

MDR = CL (clearance) x Cp (desired plasma concentration)/bioavailability

units: average dose/time

Question 24

What is the equation for loading dose?

Answer 24

loading dose = (Vd x Cp)/bioavailability

Question 25

What is the equation for Volume distribution?

Answer 25

Vd = A/Cp

Question 26

What is the equation for clearance?

Answer 26

CL = (dA/dt)/Cp = (change in concentration/change in time)/plasma concentration

Question 27

What factors are used to determine number of daily doses?

Answer 27

half-life and difference between the minimum therapeutic dose and the minimum toxic dose