Biotransformation of Drugs Flashcards
What is drug metabolism?
This refers to the biochemical modification of pharmaceutical substances (xenobiotics) with a concomitant conversion of lipophilic compounds to hydrophilic products.
What are the general characteristics of xenobiotics?
✔ Lipophilic
✔ Penetrate membranes by diffusion
✔ Transported in blood by lipoproteins
Phase I reactions:
(a) Purpose
(b) Reactions
(c) Enzymes
(a) Purpose: introduces or exposes functional groups on the drug molecule to increase its reactivity and make it more water-soluble.
(b) Reactions: common reactions include oxidation, reduction and hydrolysis
(c) Enzymes: cytochrome P450 enzymes aka. mixed-function oxidases [MFOs]
Phase II reactions:
(a) Purpose
(b) Reactions
(c) Enzymes
(a) Purpose: Increases the water solubility of the drug/metabolites to facilitate excretion.
(b) Reactions: Involve addition of endogenous molecules such as glucuronic acid, sulfate, or glutathione.
(c) Enzymes: Transferases, such as UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and glutathione S-transferase (GST)
Phase III reactions:
(a) Purpose
(b) Mechanism
(c) Outcome
(a) Purpose: Facilitates the transport of drug/metabolite conjugates out of cells and their eventual excretion from the body.
(b) Reactions: Involves various transport proteins, such as ATP-binding cassette (ABC) transporters, that actively pump the conjugates into bile or urine.
(c) Outcome: Results in the elimination of the drug/metabolite from the body, primarily via urine or feces.
Which part of the cell do Phase I, II and II reactions occur?
✔ Phase I reactions are primarily catalyzed by enzymes called cytochrome P450 enzymes, which are located in the smooth endoplasmic reticulum of liver cells.
✔ Phase II reactions occur mainly in the cytoplasm of liver cells.
✔ Phase III reactions involve transport proteins in the plasma membrane.
Briefly discus the metabolism of acetaminophen [aka. paracetamol].
(1) Phase I metabolism: Acetaminophen undergoes oxidation by the enzyme cytochrome P450 2E1 to form a highly reactive metabolite called N-acetyl-p-benzoquinone imine (NAPQI). This occurs when the usual pathways (sulfation and glucuronidation) are saturated, such as in cases of overdose.
(2) Phase II metabolism: Normally the majority of acetaminophen is conjugated with sulfate or glucuronic acid to form non-toxic metabolites that are excreted in the urine.
(3) Detoxification: The small amount of NAPQI formed is typically detoxified by conjugation with glutathione, a naturally occurring antioxidant in the liver, and then excreted in the urine.
Briefly discuss the metabolism of benzoate.
(1) Oxidation: Benzoate is first converted to benzyl-CoA by the enzyme benzoate-CoA ligase. This step requires ATP and Coenzyme A.
(2) Conjugation with Glycine: Benzoyl-CoA is then conjugated with glycine to form hippurate. This reaction is catalyzed by the enzyme glycine N-acyltransferase. Hippurate is water-soluble and can be easily excreted in the urine.
Briefly discuss the metabolism of alcohol.
◾ Alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde.
◾ The enzyme aldehyde dehydrogenase (ALDH) converts acetaldehyde to acetate.
◾ Acetate is converted to carbon dioxide and water,, which are then excreted from the body.
◾ A small percentage of alcohol is excreted unchanged through breath, sweat and urine.
Which of the following is not a Phase 1 reaction?
(a) Oxidation
(b) Hydrolysis
(c) Acetylation
(d) Deamination
(e) Hydroxylation
(c) Acetylation
Explanation:
Acetylation is a Phase II reaction.
Morphine, a powerful painkiller skips Phase 1 reaction(s) and is directly glucuronidated. Morphine is the active form of ________.
(a) acetaminophen
(b) codeine
(c) aspirin
(d) procaine
(e) heroine
(b) codeine
Which of the following statements is incorrect regarding conjugation reactions?
(a) May occur independently
(b) May occur after Phase I reactions
(c) Most of them take place in the liver
(d) After conjugation, most xenobiotics are rendered non-toxic
(e) The polarity of the xenobiotics is decreased
(e) The polarity of the xenobiotics is decreased
Which of the following enzymes is not involved in catalysing a Phase I metabolite reaction?
(a) Flavin-containing monooxygenases
(b) Glucuronyl transferase
(c) Monoamine oxidases
(d) Esterases
(e) Dehydrogenases
(b) Glucuronyl transferase
Which class of enzymes is important in the Phase 2 reactions?
(a) Amidases
(b) Reductases
(c) Esterases
(d) Acetylases
(e) Transferases
(e) Transferases
Which of the following is most correct about biotransformation of acetamiophen?
(a) It undergoes N-hydroxylation.
(b) It undergoes glucuronidation.
(c) It undergoes sulfation.
(d) Most of it undergoes Phase 2 reactions.
(e) Some of it is excreted unchanged.
(d) Most of it undergoes Phase 2 reactions.
Which of the following (Phase 1 and/or Phase 2) reactions does not participate in the biotransformation of acetaminophen?
(a) Hydrolysis
(b) Hydroxylation
(c) Glucuronidation
(d) Sulfation
(e) Glutathione conjugation
(a) Hydrolysis
Which of the following is not associated with Phase 2 reactions?
(a) Conjugation with amino acids
(b) Methylation
(c) Sulfation
(d) Glucuronidation
(e) Conjugation with oxidized glutathione
(e) Conjugation with oxidized glutathione
Explanation:
Glutathione is an antioxidant that helps protect cells from damage. It’s involved in phase II reactions, but not in its oxidized form.
Phase 2 reactions mainly occur in the ________.
(a) cytoplasm
(b) endoplasmic reticulum
(c) microsomes
(d) mitochondria
(e) all the above
(a) cytoplasm
Mixed-function oxidases are mainly localized in the ________.
(a) mitochondrial matrix
(b) plasma membranes
(c) cytoplasm
(d) microsomes
(e) peroxisomes
(d) microsomes
Those reactions that increase the toxicity of a foreign compound are known as ________ reactions.
(a) detoxification
(b) activation
(c) entoxification
(d) conjugation
(e) hydroxylation
(b) activation
Which of the following is not a Phase II substrate?
(a) glucuronic acid
(b) sulfuric acid
(c) acetic acid
(d) amino acids
(e) alcohol
(e) alcohol
Explanation:
Alcohols (and other functional groups on the drug/xenobiotic) are targets of Phase II reactions, not the molecules used in the reactions.
Which of the following is a Phase II and not a Phase I reaction?
(a) Transfer
(b) Oxidation
(c) Reduction
(d) Deamination
(e) Hydrolysis
(a) Transfer
Which of the following is not an action of the body on a drug?
(a) absorption
(b) distribution
(c) metabolism
(d) excretion
(e) side effects
(e) side effects
Which of the following is not a pharmacokinetic process?
(a) The drug causes dilation of coronary vessels.
(b) Alteration of the drug by liver enzymes.
(c) Drug metabolites are removed in the urine.
(d) Movement of drug from the gut into general circulation.
(e) The drug is deposited in fat tissue.
(a) The drug causes dilation of coronary vessels.
Explanation:
Pharmacokinetics: What the body does to the drug
It involves 4 main processes: (1) Absorption, (2) Distribution, (3) Metabolism, (4) Excretion
Pharmacodynamics: What the drug does to the body
