Intro to Pharmacology - Pharmacokinetics: Metabolism - CYP - Phase 1 Flashcards
Drug metabolism, often, but not always occurs in ____ phase(s).
2
What is phase 1 of drug metabolism?
What does it reveal?
What are the reactions?
Reveal a reactive group: -OH, - NH2
Reactions: oxidation, reduction, hydrolysis
Phase II
- _______ of the reactive group with a highly _______, ______-soluble substrate (e.g. glucuronic acid)
Reactions are?
Conjugation of the reactive group with a highly charged, water-soluble substrate (e.g. glucuronic acid)
Reactions:
- glucoronidation
- acetylation
- sulfation
- conjugation with amino acids
- conjugation with glutathione
What is the purpose of drug metabolism?
To get rid of the foreign compound by making the drug more polar, causing it to be excreted.
Which is the most common reaction of phase 1 metabolism?
oxidation
All the enzymes of phase II are of what type?
Transferases
What are the most common reactions of phase II?
Glucuronidation, acetylation
In phase 2, the transfer of a functional group is from a _________ to the drug.
co-enzyme
What are the different reactions of phase 1 metabolism and what are their enzymes’ names?
hydrolysis - hydrolase
reduction - reductase
oxidation - oxidase
If hydrolysis occurs to an ester, the enzyme is an ________.
esterase
If hydrolysis occurs to an amide, the enzyme is an ________.
amidase
Hydrolysis reactions can occur anywhere there is ______.
water
Hydrolysis generally occurs to which functional groups?
ester, peptide bond
Esters and amides are converted to what?
carboxylic acid, alcohols and amines
Esterases and amidases are found where?
What is a characteristic of these enzymes?
Found in plasma, liver, kidney, and intestine
Often are non-specific
Phase 1 - reductions
- Only a _______ number of drugs are metabolized by reduction
- Metabolites are more _________ and ready for phase II transformation
small
hydrophilic
Reduction of an aldehyde will yield?
Reduction of an alkene will yield?
Reduction of a ketone will yield?
Reduction of an alkyl halide yields?
alcohol + Hydrogen
alcohol + Hydrogen
alkene –> two extra hydrogens (both sides)
R- X –> R-H
(refer to slide 9)
Phase 1 - Oxidation
- Phase 1 reactions are often catalyzed by members of the _________ _____ family
- Other phase 1 enzymes include what?
cytochrome p450
alcohol DH
aldehyde DH
pseudocholinesterase
Low levels of aldehyde dehydrogenase leads to what?
alcohol intolerance
Low levels of pseudocholinesterase?
excessive effect of neuromuscular relaxants used during surgery
Cytochrome P450:
- contains a _____ (__) group
- absorbs light at ____ nm
- many CYP: _______ distribution of activity
heme (Fe)
450nm
polymorphic
Cytochrome p450 are found in the ____ membrane.
Cytochrome p450 is _______-associated
Cytochrome p450 has ___ coenzymes. These are?
ER membrane-associated 3 - FMN - NADPH - FADH
Why do we have a multiple copies of CYPs?
These enzymes perform redox reactions that are important for lipid metabolism, and producing FA and steroids.
CYP gene family is used in what metabolism?
Drug and lipid
Regarding CYPs, how can copy number variation be changed?
Gain: Duplication
Loss: Heterozygous deleterious SNPs
LOH: Homozygous deletions
The majority of the population has what number of proteins for a CYP?
Two functional alleles
Population based dosing is based on what?
Two functional alelles
Many drugs are metabolized by hepatic ____ ____.
This enzyme is also found in the ______ _____ and can decrease ________ even before the drug reaches the _____.
CYP 34A
intestinal wall
decrease bioavailability before reaching the liver
CYP polymorphic distribution leads to what different people?
PM - poor metabolizer
(IM) - intermediate metabolizer
EM - extensive metabolizer
URM - ultra-rapid metabolizer
For a URM patient, they tend to metabolize drugs _____ and will have a _____ plasma concentration.
quickly
low
Draw the cytochrome p450 metabolism types based on polymorphism.
Indicate any other particulars.
Refer to slide 17
Describe, very briefly, personalized medicine.
Because there are genetic differences in drug metabolic ability, the goal is to sample a patient to determine his or her genotype, and change the dose of the drug accordingly to their metabolic profile.
Cytochrome p450 - a ____-oxygenase reaction
mono
When the drug enters, it binds to what part of Cytp450?
What happens?
heme portion, drug pairs with iron-coordinating with oxygen
Iron 3 oxidized to iron 2
One molecule of oxygen moves to the drug, and one goes with hydrogen to form water.
______ ________ demonstrate decreased responsiveness to typical doses of codeine;
_____-____ _______ have suffered overdoses.
PM
URM
Why would URM suffer overdoses rather than PM in regards to codeine?
Codeine is converted to morphine. URM can rapidly and extensively convert codeine to morphine, leading to overdoses.
When talking about oxidation, how do we know the metabolic pathway the drug underwent?
During phase 1 study of pre-clinical trial, subject like monkey or healthy human takes a radiolabelled drug, excreted in urine or feces and analyzed to determine enzymes involved.
What is the general reaction of oxidation of drugs?
Drug-H + O2 + 2H+ + 2 e- –> Drug-OH + H2O
Is acetaminophen safe?
Yes, for the most part.
However, after phase 1 metabolism, it is converted to a toxic compound which, for the most part, is converted by phase 2 metabolism to a safe compound.
What are the different phase 1 oxidation reactions?
Aromatic Aliphatic Epoxidation Oxidative de-alkylation Oxidative de-amination
Describe aromatic oxidation?
adding OH to para-position
(i.e. addition of OH to opposite side of benzene ring
Describe aliphatic oxidation.
Adding OH to the end of the alkyl group (primary alcohol)
Describe epoxidation.
Adding - O-group to C=C, then further into (OH)-C-C-(OH)
Describe oxidative de-alkylation.
Alkyl group is removed, the hetro-atome (N, S, O) has H instead
Describe oxidative de-amination.
NH2 is removed, the carbon that N-previously attached become C=O
Look up the structure of acetaminophen and draw out the end product of N-oxidation.
refer to slide 23
Look up the structure of phenobarbitone and draw out the end product of aromatic oxidation.
refer to slide 24
Look up the structure of pentobarbitone and draw out the end product of aliphatic oxidation.
refer to slide 25
Look up the structure of carbamazepine and draw out the end product of epoxidation.
refer to slide 26
Look up the structure of Imiparmine and draw out the end product of N-oxidative dealkylation.
refer to slide 27
Look up the structure of Phenacetin and draw out the product of Oxidative dealkylation.
refer to slide 28
Look up the structure of Amphetamine and draw out the product of oxidative deamination.
refer to slide 29
Draw out the reaction of a primary alcohol converted by ADH.
refer to slide 30
Draw out the reaction of an aldehyde converted by ADH.
refer to slide 30
Draw out the reaction of a secondary alcohol converted by ADH.
refer to slide 30
What is the common point of all NTs?
Amine group
For the NTs that have benzene rings, what is their precursor?
Tyrosine
What is the basic equation of N-oxidation?
Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O
What is the basic equation of aromatic oxidation?
Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O
What is the basic equation of aliphatic oxidation?
Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O
What is the basic equation of epoxidation?
Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O
What is the basic equation of oxidative dealkylation of drugs?
Drug-X-CH3 + O2 –> Drug-X-CH2OH –> Drug-XH + HCHO
In oxidative dealkylation, what is the alkyl chain attached to?
X = N, O or S
Oxidative dealkylation is a ___-step process.
two
In what cases would oxidative dealkylation occur more than once?
with tertiary amines for example
For the drug phenacetin (slide 28), what two reactions are feasible?
amidase reaction
or oxidative dealkylation
What is the basic equation of oxidative deamination?
Drug-NH2 + O2 –> Drug-CO-R + NH3
ADH levels are high in what organs?
GI and kidney
What is the enzyme that oxidizes the different NTs?
MOA - monoamine oxidase
MOA inhibitors will lead to accumulation of what?
Not only serotonin but the other NTs
What is the basic equation of MOA?
RCH2NH2 –> RCHO
Draw serotonin undergoing Monoamine oxidase conversion.
refer to slide 32
Induction and inhibition of CYP:
- Some _____ or _____ types can induce or inhibit CYP activity
- altered normally expected level of drug concentrations
- given drugs could result in ____ or ____ pharmacological action
- could lead to ________ _______
- need a close monitoring mechanism
food or drugs
more or less
unexpected toxicity
Grapefruit juice inhibits what?
Intestinal CYP34A
What will grapefruit juice do?
Inhibits CYP34A, thereby increasing the amount of drug that reaches the liver and the systemic circulation
Describe how CYP34A will reduce bioavailability.
Occurs prior to first-pass metabolism.
CYP34A lines intestinal tract, will oxidize the drug, making it more polar and reducing available drug.
Does grapefruit juice affect first pass metabolism?
No, the enzymes there are less sensitive to grapefruit juice in the liver
How does grapefruit juice affect Cp?
Increases it
What is another compound that will reduce bioavailability of certain drugs through its activity on CYP450?
St. John’s Wort
