Module 4 Flashcards
Enzyme-mediated alteration of a drug’s structure
Metabolism
What are the different sites of drug metabolism?
Liver, intestine, stomach, kidney, intestinal bacteria
What is another term for metabolism?
biotransformation
What is the primary site of drug metabolism?
The liver
What are some common exogenous toxins?
Meat, wine/alcohol, cigarettes, coffee, drugs, vegetables
What are the different therapeutic consequences of drug metabolism?
Increase water solubility of drugs to promote their excretion Inactivate drugs Increase drug effectiveness Activate pro-drugs Increase drug toxicity
What are some essential endogenous molecules provided by metabolism?
Vitamin D, bile acids, cholesterol, steroids, bilirubin
In most clinical situations, drug metabolism follows ____ order kinetics
first
Describe first order kinetics.
There is more enzyme than drug; therefore drug metabolism is directly proportional to the concentration of free drug
In first order kinetics, a constant _______ of drug is metabolized per unit time.
fraction
Describe zero order kinetics.
Plasma drug concentration > enzymes
Drug metabolism is constant over time
In zero order kinetics, a constant ________ of drug is metabolized per unit time.
amount
What is the best example of zero order kinetics?
Ethanol
In this metabolism kinetics, drug metabolism is independent of drug concentration.
Zero order
Where can first pass metabolism occur?
Hepatocytes in the liver
intestinal enterocytes
Stomach
Intestinal bacteria
What is the result of 1st pass metabolism?
A decreased amount of parent drug that enters the systemic circulation
What is an example of first pass metabolism in the stomach?
Alcohol –> Alcohol DH –> acetaldehyde
High ER drugs
- have _____ oral bioavailability (-%)
- PO does are usually ______ than IV doses
- _____ change sin hepatic enzyme activity produce _______ changes in bioavailability
- ______ susceptible to drug-drug interactions
low - 1-20%
higher (much)
small, large
very
Low ER drugs
- have _____ oral bioavailability
- PO doses are ______ to IV doses
- ______ changes in hepatic enzyme activity have _______ effect on bioavailability
- __ ______ susceptible to drug-drug interactions
- Take ______ passes through the liver via the systemic circulation before they are completely metabolism
high similar small, little not very many
What are the two phases of drug metabolism?
Phase I and Phase II
Phase I metabolism
- Convert _______ drugs to more ______ molecules by ________ or ________ polar functional groups such as ______ or ______
lipophilic, polar, introducing or unmasking
hydroxyl, amines
What are the different types of reactions in phase I metabolism?
Hydrolysis, oxidation, reduction
Phase I metabolism is mediate by what enzymes?
Cytochrome p450 enzymes (main), esterases, dehydrogenases
Describe the activity of the resulting metabolites of phase I metabolism.
More active, less active or equally as active as the parent drug
Phase II metabolism
- Increases the _______ of ________ drugs by _______ reactions
polarity, lipophilic, conjugation
What are different conjugates of phase II metabolic reactions?
Glucuronic acid, sulfate, acetate or amino acids
Describe the activity of metabolites of phase II metabolism.
Less active than the parent drug - except morphine-6-glucuronide (more potent analgesic than morphine)
Where is the intracellular site of phase I drug metabolism?
Phase I drug metabolizing enzymes are localized to the smooth endoplasmic reticulum
Where is the intracellular site of phase II drug metabolism?
Phase II drug metabolizing enzymes are localized predominantly in the cytosol of the cell; except with glucuronidation, which is localized to the smooth ER
Largest family of drug metabolizing enzymes.
CYPs (Cytochrome P-450)
The majority of drug metabolism in the body is performed by _______ CYP enzymes.
CYPs are the predominant phase ___ drug metabolizing enzyme system.
hepatic
phase I
How do CYP enzymes work, i.e. metabolize?
Oxidize drugs by adding oxygen, producing water as a by-product
How does malnutrition affect CYP activity?
Can decrease it as these enzymes require dietary protein, iron, folic acid and zinc for full activity
Describe the nomenclature of CYP enzymes.
CYP3A4 for example.
3 - family
A - sub-family
4 - isozyme
_________ metabolizes the largest fraction of currently marketed drugs.
CYP 3A4
What are the different phase II drug metabolizing enzymes?
UDP-glucuronosyltransferases (UGTs) Sulfotransferases (SULTs) Glutathione S Transferases (GSTs) N-acetyltransferases (NATs) Thiopurine Methyltransferases (TPMT)
Which phase II drug metabolizing enzyme type metabolizes drugs the most?
The fraction of drugs metabolized is equally split between UGTs, SULTs, GSTs, and NATs
Where are UGTs localized?
What do they catalyze transfer or?
Describe the effect of the enzyme on the parent drug.
How many UGT enzymes are there in humans?
Smooth ER
glucuronic acid
Glucuronidated drugs are more polar and more easily excreted
19
Where are SULTs localized?
What do they add?
Describe the metabolite.
How many SULT enzymes are there in humans?
Cytosol
Add sulfate to hydroxyl groups of drugs
Sulfated drugs are more polar and more easily excreted
11
Where are GSTs localized?
What do they add?
What is the result of transfer?
How many GSTs are there in humans?
Cytosol (main) or microsomal
Add GSH (glutathione)
Intracellular anti-oxidant –> causes a reactive drug to be less toxic
20+
Where are NATs localized?
What do they add?
What are they subject to?
How many are there in humans?
Cytosolic
Acetyl group from Acetyl-CoA
Subject to genetic polymorphisms - variability in drug response
2 - NAT1 and NAT2
Where are TPMTs localized?
What do they add?
What are they subject to?
Cytosolic
Add methyl from S-adenosylmethionine
Subject to genetic polymorphisms, can have dramatic effects on drug safety
What are the major factors that affect drug metabolism?
Age
drug interactions
disease state
Genetic polymorphisms
Describe how age affects metabolism.
Infants have almost no hepatic CYP activity - takes babies approx. 1 year after birth until they have a reasonable level of drug metabolizing enzymes
By age 2 - same level as adults
Process where a cell synthesizes an enzyme in response to a drug or other chemical.
Enzyme induction
Consequence of CYP induction.
Increased drug metabolism
What are consequences of increased drug metabolism?
Decreased plasma concentration
Decreased drug activity
Increased drug activity
_______ induces some drug metabolizing enzymes
smoking
What is the consequence of CYP inhibition?
Decreased drug metabolism
Decreased drug metabolism has the following consequences.
Higher plasma concentration
Increased therapeutic effect
Increased drug toxicity
What are diseases that decrease CYP activity?
Liver disease
kidney disease
inflammatory diseases
infection
SNPs affect what?
the protein
What are the common phase I SNPs?
CYP2C9
CYP2D6
What are the common phase II SNPs?
UGT1A1
NAT2
CYP2C9 metabolizes what? Polymorphism results in what? Describe the effect on dosage. What may occur if the dosage is not altered?
Metabolizes warfarin
Polymorphism results in decreased activity/metabolism
Dosage must be lowered in these patients, else extensive bleeding may occur
CYP2D6
Metabolizes what?
What phenotypes are possible?
Codeine to morphine
URM, EM, IM, PM
Describe EM.
Extensive metabolizers - considered to have normal enzymatic activity
Describe IM. PM.
IM - lower metabolic activity
PM - almost no metabolic activity (i.e. no pain relief)
Describe URMs.
Ultra-rapid metabolizers - significantly increased CYP2D6 activity - possess multiple copies of CYP2D6 gene
UGT1A1
Metabolizes what?
Polymorphisms cause what?
What are patients with the polymorphism at increased risk of?
Metabolizes SN-38 - anti-cancer compound (inactivates)
Polymorphisms decrease its activity
Patients with UGT1A1 are at increased risk for diarrhea and dose-limiting bone marrow suppression
NAT2
Metabolizes what?
Number of polymorphisms here?
Possible phenotypes?
Metabolizes isoniazid (TB), caffeine, cancer causing chemicals
23+
Rapid or slow acetylators
Describe slow acetyaltors and the effect with isoniazid.
More susceptible to isoniazid toxicity (neuropathy, hepatotoxicity) - higher risk of developing certain types of cancers
