Drug metabolism Flashcards
First pass effect dosing
Need higher concentration orally vs. IV
Liver metabolism responsible for this
Phase 1
Oxidation, reduction, hydrolysis
cytochrome P450 enzymes (CYPs)
Mostly adds hydroxyl
Lots of energy
Phase 2
Conjugation
glutathione S-transferases, sulfotransferases, UDP glucuronic acid transferases
Lower in energy
CYP3A4
Most abundant
Acetaminophen, lovastatin, felodipine
Many adverse reaction involve inhibition of this
CYP2C9/19
Second most common
CYP2D6
Only 4% of total content but 30% of drug metabolism
Highly polymorphic
Tamoxifen
Conjugation
Formation of metabolite with increased molecular mass,..biological activity terminated
Glutathione S transferases
Protect cells from oxidative damage by transferring glutathione to electrophils
Lack of glutathione leads to oxidative damage and liver failure
IMportant in acetaminophen and anti cancer drug resistance
Affected by alcohol abuse
UDP-glucuronosyl transferases
Billirubin homeostasis
Billirubin peaks 3-4 days after born because of delayed expression of enzyme
N-acetyl transferases
Metabolize drugs with aromatic amine or hydrazine
Thiopurine methyltransferase
Methylation of thiopurine drug 6-mercaptopurine
6-mercaptopruine used to treat
Leukemia and Crohn’s
Acetaminophen phase 1 and 2
Could be glucuronidated or sulfated during phase 1
Creates toxic metabolite
Glutathione S transferase will add glutathione and make neutral
If alcohol present, increases CYP2E1 and decreases glutathione and increases metabolite that destroys hepatocytes
Antidote to acetominophen poisoning
N-acetylcysteine helps body make more glutathione
Phase 3 metabollism
Transport of drugs into or out of cells
Hepatic metabolism
Transport into hepatocytes and excretion into bile
Oral bioavailability
Transport into enterocytes and excretion into intestinal lumen
Renal clearance
Transport into proximal tubular cells
Excreted into tubular lumen
BBB
Restricts entry of drugs to CNS
MDR1
Luminally expressed efflux transporter in the GI, liver, brain, kidney
Maintains low concentrations of substrates
Upregulated in tumor cells to decrease effect of chemo
Used in the kidney and liver to get into urine and bile
Prodrug
Must be cleaved in order to become a product
Product could have higher potency than the original so overactivation of enzyme that breaks down (cytochrome p450) could lead to overdose
6-mercaptopurine
Prodrug used to treat leukemia and Crohn’s
TPMT will inhibit incorporation of the drug into DNA (needed to work)
Fewer TMPT mean maybe too much into DNA
Tamoxifen
Needs to be cleaved by CYP3A4/5 and CYP2D6 in order to become endoxifen active form
Could go through either enzyme first/second
Drug activation of CYP450s
Activates nuclear receptor PXR…has longer effect than inhibiton
Inhibition of CYP450s
Drug binds to the enzyme
Enzyme induction typially due to
Amount of enzyme made in the liver
Peak 4-14 days and back to normal in 1-3 weeks
Inducing CYP450s will cause
A decrease in drug effect
St Johns Wort drug interaction
St Johns wort increases expression of CYP3A4 activity…this breaks down felodipine normally so if you’re taking St Johns Worst and Felodipine, concentration of felodipine will be lower
In inhibition of drug metabolism
Efficiacy of drug decreased (think prodrugs)
Toxicity of parent drug increased
Stimulation of drug metabolism
Efficacy of drug decreased and toxicity of the metabolite is increased
Lovastatin
Targets hepatocyte in the liver Metabolized by CYP3A4 Requires transporter SLCO1B1 Adverse effects include myopathy Symptoms include muscle pain
What increases lovastatin concentrations
CYP3A4 inhibitors (grapefruit juice, intraconozole)
Itraconzole/felodipine interaction
Intraconazole used to treat fungal infections…inhibits CYP3A4…Felodipine for high blood pressure…Felodipine is CYP3A4 substrate…adverse effects associated with low blood pressure (headaches)
Will kick up HR
Grapefruit juice
Inhibits CYP3A4 and can increase felodipine and statin concentrations
St Johns wort
Increases CYP3A4 expression and can increase clearance of drugs
Polymorphisms can effect
Clearance of drugs
CYP2D6 polymorphisms
Poor metabolizers
IM metabolizers
Ultrarapid metabolizers
Extensive (normal) metabolizers
CYP2D6 and tamoxifen
Women with deficient CYP2D6 are at heightened risk of tx falure…can’t convert to endoxifen
Amplichip can help test for this
undecided whether this actually help
Polymorphism in Thiopurine methyltrasnferase
problems with 6-mercaptopurine response
If wild/wild - then decreased toxicity but increased risk of relapse…higher Intracell concentration
If mutant/mutant - increased myelosupprresion and increased risk of secondary cancer…lower intracell concenrtaton
Statins and SCLO1B1
If transport is low, then lovastatin is poorly metabolized and systemic circulation high…means that increased risk of myopathy
Age and drug metabolism
Less than 1 month and older than 65 are lower (decreased CYP activity)
Elderly also have decreased renal funciton and decreased hepatic blood flow
Gender and drug metabo
Females have greater risk of developing abnormal response…due to lots of things included phase 1,2, and transporter
Two enzymes higher in females
CYP2D6 and CYP3a
Liver dz and drug metabolism
Cytochrome P450 decreases as liver function decrewases
Glucuronidation is less affected but can be affected in severe cases
Obesity and drug metabolism
Often develop fatty liver
Increase CYP2E1, decrease CYP3A, and increase UDPGT
Could impact volume of distribution and clearance
Felodipine important
CYP3A4 substrate
Iraconazole important
CYP3A4 inhibitor
6-mercaptopurine important
TPMP substrate and prodrug
Lovastatin important
CYP3A4 substrate and SCLO1B1 substrate
St John’s Wort important
CYP3A4 inducer
Tamoxifen important
CYP2D6 substrate and a prodrug
