Phase 1 and Phase 2 Rxns and pharmacogenomics Flashcards
Phase 1 rxns
focused on adding or unmasking polar groups such as (OH, NH2) If a molecule has a methoxyl group, it will remove it leaving the hydroxyl.
P1 rxns can either be
oxidation or Hydrolysis reduction
P1 rxns will generate products that are either
electrophiles or nucleophiles
For a phase 2 reaction, the nucleophiles generated from phase 1 reaction will undergo
sulfonation
acetylation
glucuronidation
For a phase 2 reaction, the electrophiles generated from phase 1 reaction will undergo
Glutathione conjugation
Cytoplasm is a - environment
Reducing
Exception to P1—>P2
Ionizide undergoes acetylation and then hydrolysis
Ethanol and nicotine usually
speed up the metabolism of other drugs
Ethanol is given for methanol poisoning, why?
Ethanol induces stimulation of liver enzymes in order to get rid and metabolize the methanol.
Molecule in grapefruit juice
furanocoumarin
Tylenol can undergo
Glucuronidation or sulfonation
A class of enzymes known as ? will ? Tylenol.
Monooxygenase hydroxylation. This will oxidize Tylenol. And can be a harmful electrophile.
Molecule given for Tylenol overdose
N-Acetylcysteine – This has a very potent sulfhydryl group to react with the potent electrophile. Must be given early so that it does not interact with other molecules.
How to smartly use drug metabolizing enzymes and issues that may arise.
First pass effect may result in the molecules becoming inactive. Design a molecule that will be activated as metabolism goes on.
Tamoxifen is used to treat breast cancer , tamoxifen is a
prodrug, and endoxifen is the pharmacologically active drug.
This is a highly polymorphic cytochrome
CYP2D6
Codeine is a prodrug used an an analgensic, broken down by
CYP2D6
- Ultrarapid
- Extensive
- Intermediate metabolizer
- Poor metabolizer
- more than two copies of functional allele
- two functional alleles
- one reduced and one nonfunctional
- no functional alleles
Hawaii lawsuit enzyme and drug
Clopidogrel and CYP2C19 (<15%)
Clopidogrel and SR26334 (> 85%)
Used in treatment of colorectal cancer
Fluorouracil -Enzyme is DPD-Dihydropyrimidine Dehydrogenase
Example of using first pass effect to advantage
Loratadine metabolized to Descarboethoxyloratadine
More alpha-2 receptors means
more likely to develop nicotine addiction
Four focuses on drug metabolism
- Genetic variations in enzymes
- ” “ “”” transporters
- ””””” immune system function
- polygenic effects
Codeine is
lipophilic and can cause opioids to pass through the breast milk and target breathing center of the brain.
If metabolism is ultra rapid to clopidogrel this can cause
increased bleeding
Irinotekan
used to treat colorectal cancer. To rid of this molecule, polar groups must be attached. You accumulate higher concentrations of metabolites. Slow metabolism leads to toxicity. Enzyme is UGT1A1
Mediterranean populations should not eat broad beans because
G6PD deficiency leads to lower levels of NADPH leading to a person being unable to deal with certain molecules that cause oxidative stress on erythrocytes and may result in hemolysis.
For this same reason, Rasburicase can increase uric acid. Rasburicase breaks down uric acid to either allatonin(non toxic) or hydrogen peroxide (oxidative stress).
statins work to
lower cholesterol
Metabolism of statins
transported to hepatocytes via transporters
If a patients transporters are not effective then an increase in concentration will cause potential myotrophy.
Transporter associated with statins
OATp1B1
Very susceptible to a certain class of drugs that contain sulfonamides
Polymorphism in Human Leukocyte antigen
results in Stevens-Johnson Syndrome
Used in the treatment of epilepsy, people in East Asia may have sensitivity to these drugs.
Carbamazepine
Warfarin is an anticoagulant developed from natural products
Cumurin
Enzymes involved in warfarin metabolism
CYP2C9 and VKORC1
