PPT 4 Flashcards
What is the primary biotransformation organ?
Liver - hepatocytes
Describe the first-pass effect of oral medications
Hepatic portal system
GI → local veins (intestinal capillaries) → hepatic portal vein (combines with splenic vein)→ Sinusoids (very leaky capillaries) → Hepatic vein → Vena cava → Systemic Circulation
Describe the route an IV medication takes in regards to hepatic blood flow
Systemic Circulation → hepatic artery → Sinusoids → Hepatic vein → Vena cava → Systemic Circulation
Hepatic portal vein and hepatic arteries combine to form ________
sinusoids
Describe the oxygenation of the blood in the sinusoids
Mixture of deoxygenated blood from heaptic portal vein and oxygenated blood from hepatic artery
Lower oxygen environment, lower than systemic circulation
________ are the cells that absorb a drug from leaky sinusoids, where biotransformation takes place
Hepatocytes
What are the reactions the liver uses to complete biotransformation?
Phase I and phase II reactions - help with clearance or excretion of drug
Differentiate between phase I and phase II reactions
Phase I - make drug more polar
- add or unmask a functional group on an enzyme (small)
Phase II - conjugation reactions, often detoxifying
- adding bigger molecules on drug (glucuronidation)
What are the 4 phase I reactions?
Oxidation, reduction, dehydrogenation, and hydrolysis
The vast majority of drugs are modified by _______ in phase I reactions
oxidation
Describe the steps to cytochrome P450 oxidation
- Drug binds to CYP
- CYP is reduced by flavoprotein (P450 reductase)
- Flavoprotein is reduced by NADPH - Oxygen attaches to CYP
- Oxygen attached to drug, CYP is oxidized
- Oxidized drug is released (more hydrophobic with -OH instead of -H)
30% of drugs undergoing phase I reactions are oxidized by ________
CYP3A4 - substrate specificity low
- 50% of oxidation reactions
What are the 3 most important cytochrome P450 types?
CYP3A4, CYP2D6, and CYP2B6
2B6 < 2D6 < 3A4
B less than D, 2’s less than 3
Cytochrome 450 enzymes are _________
oxidases
Cytochrome p450 oxidation occurs in the ________ of the hepatocyte
Sarcoplasmic endoplasmic reticulum
How is the WT indicated?
*1 - most commonly seen in population
- everything else is mutant
Polymorphic variants
mutations from the WT that can have greater, less, or the same amount of activity of the WT (*1)
Drugs that increase cytochrome P450 activity
induction
Drugs that decrease or irreversibly inhibit cytochrome P450 activity
inhibition
Cytochrome P450 induction causes a decreased drug effect – IF metabolism ________ drug
deactivates
Cytochrome P450 induction causes an increased drug effect – IF metabolism ________ drug
activates
Cytochrome P450 inhibition causes an increased drug effect – IF metabolism ________ drug
inactivates
Cytochrome P450 inhibition causes a decreased drug effect – IF metabolism ________ drug
activates
If a patient who is on warfarin eats a lot of Brussel sprouts, what effect would they have on the medication? (Brussel sprouts are an inducer of CYP1A2 and warfarin is inactivated by CYP1A2)
A lot more inactivation of warfarin - less effect of medication
What are the 7 types of conjugation?
glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfation, methylation, and water conjugation
What is the most important type of conjugation?
glucuronidation
How do uridine diphosphate glucuronyltransferases (UGTs) glucuronidate a drug?
Uridine diphosphate (carrier molecule) adds glucuronic acid to drug
Glucuronidation and Glutathione-S-transferase (GST) make a drug more _______ and increase _______
Water soluble, urinary excretion
How does Glutathione-S-transferase (GST) work?
Adds glutathione to a xenobiotic (drug) to make it more water-soluble (detoxification)
What is a therapeutic dose?
Normal detox pathways functional – no toxic byproducts
What is overdose?
Overwhelm normal pathways, alternative pathways activated – toxic by-products
How does a Tylenol overdose occur?
- occurs when limited amount of glutathione exhausted
- nucleophilic toxic intermediate binds to cell macromolecules (proteins, cell membrane, carbohydrates) and inactivates them.
- leads to liver cell death
What are the normal pathways for Tylenol metabolism?
Normal pathways: Phase 2 - glucuronidation and sulfation, creating nontoxic byproducts.
What occurs when Tylenol is given in toxic doses?
- Phase 1 - CYP2E1 and CYP3A4, creates reactive toxic intermediates
- Phase 2: glutathione conjugation- binds to nucleophilic intermediate to neutralize (backup to toxic pathway)
What are the 3 examples of personalized medicine?
6-MP - TPMT mutations, warfarin - CYP2C9, herceptin - HER2 overexpression
The Goal of Personalized Medicine
- The Right Dose of
- The Right Drug for
- The Right Indication for
- The Right Patient at
- The Right Time
Alternative forms of a gene which occur at the same locus
Allele
All of the variant forms of a gene that are found in a population
Genetic testing is _______ for herceptin treatment of breast cancer
required
Genetic testing is _______ for warfarin treatment
recommended
Describe the variations in drug response based on pharmacogenomics for 6-MP
- WT - normal metabolism
- Heterozygous mutant - metabolize drug slower
- Homozygous mutant - extra slow metabolizer (TPMT deficient); can be fatal
Describe the pharmacogenomics for Warfarin - CYP2C9
Racemic mixture - (S) much more potent than (R)
- (S) metabolized by CYP2C9
- If mutation in CYP2C9, warfarin won’t work very well
- WT, heterozygous mutant, homozygous mutant
- mutants have reduced metabolism and higher warfarin concentrations → more likely to bleed out
- (R) metabolized by CYP2C19
How does herceptin work in treating breast cancer?
Herceptin aka trastuzumab is a monoclonal antibody that binds to and shuts down the HER2 receptor
- If patient not HER2+, herceptin won’t do anything
