Chemical Pathways of Drug Metabolism Phase I and II Flashcards
What type of metabolism occurs before the drug reaches systemic circulation?
Pre-systemic metabolism
What is the most commonly seen metabolizing enzyme in the blood?
Esterases
What are the two major classifications of drug metabolism?
Hepatic and extra-hepatic
What are the two common sites of pre-systemic metabolism?
GI tract and liver
Which CYP enzyme is the major one found in the GI?
CYP3A4
Which CYP enzymes are polymorphic?
All to a certain degree
Where can esterases be found?
Blood, liver, GI tract
Which phase II enzymes are polymorphic?
UGTs largely, TPMT, NAT1, NAT2, GSTs (M,T,P,A)
Where is enzyme CYP2E1 most commonly expressed?
Lungs
Major con of CYP2E1?
Metabolizes procarcinogens in the body
What factor largely affects how much of an enzyme each individual expresses?
Genetic factors
Which enzyme shows increased activity due to inflammation?
CYP2E1
Which 2 CYP enzymes are commonly affected by a deleted gene mutation?
CYP2D6 and CYP2C19
The expression of which 5 CYP enzymes can be either be increased or decreased by polymorphism?
CYP2D6, CYP2C19, CYP2C8, CYP2B6 and CYP2A6
What is the main purpose of metabolism?
Make the drug more water solubility, making excretion possible
What is the primary method of excretion for Phase I metabolic waste?
Urine
What is the primary method of excretion for Phase II metabolic waste?
Feces
True or false: Non-polar conjugates are commonly excreted in the urine
False. Non-polar conjugates are commonly excreted in the feces, and polar metabolites in the urine
In what case may a drug directly undergo Phase II metabolism?
The drug already contains a functional group (biological marker) identifying it should undergo Phase II metabolism
Exceptions to the Phase II metabolism rule
Methylation and acetylation. Decrease water solubility
What is the major Phase I reaction?
Oxidation
Which of the following is not a Phase I reaction? .Oxidation .Methylation .Hydrolysis .Reduction
Methylation
What non-CYP enzyme is highly responsible for oxidation reactions?
Monoamine oxidase (MAO)
What is the most common Phase II reaction?
Glucuronidation
True or false: 95% of oxidation reactions are catalyzed by CYP enzymes
True
Which enzyme converts codeine to morphine?
CYP2D6
True or false: If morphine is administered, it will undergo Phase I metabolism
False. Morphine undergoes Phase II metabolism. If codeine is administered, it undergoes Phase I metabolism and is converted to morphine
True or false: Deamination of a terminal amine forms a ketone
False. It forms a carboxylic acid
True or false: Deamination of a penultimate amine forms a ketone
True
True or false: Formation of both ketones and carboxylic acids after metabolism will increase water solubility
False. Formation of ketones decreases water solubility
What are the 3 Phase I reactions from most to least occurence?
Oxidation, hydrolysis, reduction
Which two enzymes are highly responsible for hydrolysis?
Esterases and amidases
True or false: Amidases and esterases are both highly suited for drug metabolism
False. Amidases are mostly suited for protein and peptide metabolism
Glucuronidation at the carboxylic acid group, or _____________, is the least common form of glucuronidation
Acylglucuronidation
True or false: GSSG is the active form of glutathione because it has a free thiol group
False. GSH is the active form
True or false: Glutathione undergoes conjugation in the presence of enzymes or nucleophiles (electron donating groups)
True
What is the most commonly seen type of amino acid conjugation?
Glycine conjugation
Glycine conjugation is the major metabolic route for xenobiotic ________ _______
Carboxylic acids
Why should newborns not receive anything containing benzoic acid preservatives?
Their glycine conjugation pathway is underdeveloped, therefore, preparations containing preservatives can lead to toxicity
Why are methylation and acetylation considered Phase II reactions?
These processes add on functional groups (conjugate), despite decreasing water solubility
Imipramine can undergo all metabolic transformations except: Oxidative Deamination Oxidative N-Dealkylation Hydrolysis Aromatic Oxidation Glucuronide conjugation
Hydrolysis
Which of the following structural features must be present in an organic compound for it to undergo amino acid conjugation? Amines Alcohols Epoxides Esters Carboxylic acids
Carboxylic acids
Highly lipophilic amine containing compounds undergo N-dealkylation at an (inc/dec) rate
Increased
