Pharmacogenomics Flashcards
Phase I enzymes
CYP2D6, CYP2C19, CYP3A4 and CYP3A5, Dihydropyrimidine Dehydrogenase (DPD), CYP2C9 and VCORC1
What family of enzymes is involved with functionalization in phase I?
P450 enzymes
What family of enzymes is involved in conjugation of phase II?
transferases
Functionalization
a functional group is added to a drug, causing it to become ionized
conjugation
large polar group is added to the functional group of a drug and becomes much more polar and easy to excrete
What is metabolism for?
removing foreign molecules from the body
enzyme induction
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
p-glycoprotein
ATP-dependent drug efflux transporter (pumps drugs out of the cell) with broad substrate specificity. Causes reduced efficacy of drugs.
How does drug-drug interaction occur through drug absorption?
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.
PXR/PXR
nuclear receptor that senses the presence of foreign molecules and up-regulates the expression of proteins that clear these molecules from the body
AhR cytoplasmic receptor
ligand-activated transcription factor that regulates cytochrome P450.
How do drug-drug interactions occur via drug excretion?
increase renal blood flow and therefore increasing glomular filtration rate
inhibit active tubular secretion
alter tubular reabsorption
What is the basis of pharmacogenomics?
genetic variants (SNPs, indels, CNVs) between patients leads to varied response to drugs between patients
What happens if the pH is higher than the pKa of a weak acid drug?
drug is deprotonated and charged due to more basic environment, and is cleared more easily from the body
How is renal excretion controlled?
via adjusting urine pH
How are drugs excreted via the biliary tract?
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
How does renal excretion work?
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
Examples of zero-order kinetics drugs
ethanol, phenytoin, aspirin
First order elimination characteristics
elimination rate proportional to drug plasma concentration
has a half-life
zero order elimination characteristics
elimination rate is constant
process is saturated (does not change with concentration changes)
What is clearance a measure of?
efficiency of irreversible removal of a drug by an elimination organ
What is the equation for half-life?
t1/2 = (0.7 x Vd)/CL
What is the equation for maintenance dosing rate?
MDR = CL (clearance) x Cp (desired plasma concentration)/bioavailability
units: average dose/time
What is the equation for loading dose?
loading dose = (Vd x Cp)/bioavailability
What is the equation for Volume distribution?
Vd = A/Cp
What is the equation for clearance?
CL = (dA/dt)/Cp = (change in concentration/change in time)/plasma concentration
What factors are used to determine number of daily doses?
half-life and difference between the minimum therapeutic dose and the minimum toxic dose
