Module 4 Flashcards
Define kinetics
the branch of chemistry or biochemistry concerned with measuring and studying the rates of reactions
What is drug metabolism and the purpose of drug metabolism?
Metabolism is the enzyme mediated alteration of a drug’s structure.
Drug metabolism is the term used to describe the biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily.
Sites of drug metabolism include what?
Liver, intestine, stomach, kidney, intestinal bacteria
Where is the primary site of drug metabolism?
Liver
What in the intestine are able to metabolize drugs?
Enterocytes that line the gut
Why do we need drug metabolism?
Drug metabolism is important in humans to protect us from a number of environmental toxins as well as synthesize essential endogenous molecules.
What are some examples of endogenous molecules synthesized by drug metabolizing enzymes?
- Vit D synthesis
- Bile Acid synthesis
- Cholesterol metabolism
- Steroid hormones
- Bilirubin
What happens to a drug after it has been metabolized (therapeutic consequences of drug metabolism)?
Varies between drugs.
Therapeutic consequences of drug metabolism are summarized below:
1) Increase water solubility of drugs to promote their excretion
Lipophilic to Hydrophilic
2) Inactivate drugs
Active to Inactive
3) Increase drug effectiveness
Active to More active
4) Activate prodrugs (prodrugs are inactive until metabolized)
Prodrug (inactive) to Active drug
5) Increase drug toxicity
Non-toxic to Toxic
Most drugs in clinical use exhibit what (in regards to kinetics of drug metabolism)?
First order kinetics
Describe first order kinetics
- In most clinical situations the concentration of a drug is much lower than the metabolic capacity of the body. In these situations drug metabolism displays 1st order kinetics.
- In 1st order kinetics drug metabolism is directly proportional to the concentration of free drug.
- This means a constant fraction of drug is metabolized per unit time.
Describe zero order kinetics
- In zero order kinetics, the plasma drug concentration is much higher than the metabolic capacity of the body.
- One of the best examples of zero order kinetics is ethanol.
In which kinetics is drug metabolism constant over time?
Zero order kinetics.
This means a constant amount of drug is metabolized per unit time.
Metabolism is also referred to as what?
biotransformation
What are prodrugs?
prodrugs are inactive until metabolized
Define metabolite
a substance formed in or necessary for metabolism
What is one of the less favourable consequences of drug metabolism?
It could in some cases increase drug toxicity
PO drugs may undergo significant metabolism prior to entering the systemic circulation, this is called what?
first pass metabolism
Where can first pass metabolism occur?
- Hepatocytes in the liver
- Intestinal enterocytes
- Stomach
- Intestinal bacteria
What is the result of first pass metabolism?
decreased amount of parent drug that enters systemic circulation
Describe extraction ration (ER)
Drugs are characterized as having high or low extraction ratio (ER) depending on how much metabolism occurs on the first pass through the liver.
What are the characteristics of high ER drugs?
- Have low oral bioavailability ( 1- 20%)
- PO doses are usually much higher than
IV doses (to compensate for high first
pass metabolism). - Small changes in hepatic enzyme
activity produce large changes in
bioavailability. - Very susceptible to drug-drug
interactions
What are the characteristics of low ER drugs?
- Have high oral bioavailability ( > 80%)
PO doses are usually similar to IV doses. - Small changes in hepatic enzyme
activity have little effect on bioavailability. - Not very susceptible to drug-drug
interactions. - Take many passes through the liver via the systemic circulation before they are completely metabolized.
True or False: In low ER drugs, PO doses are usually similar to IV doses?
True
Phase I metabolism is mediated by what?
CYP450 enzymes primarily and also esterases and dehydrogenases
What is the primary purpose of Phase I metabolism?
Convert lipophilic drugs to more polar molecules by introducing or unmasking polar functional groups such as hydroxyl (-OH) or amine (-NH2).
Which reactions does Phase I metabolism involve?
Involves oxidation, reduction and hydrolysis reactions
What is the primary purpose of Phase II metabolism?
Increase the polarity of lipophilic drugs by conjugation reactions (addition of large water soluble molecule to drug; very similar purpose to phase I)
Define conjugate
a substance formed by the reversible combination of two or more others - the addition of large water soluble molecules to a drug
What is the possible outcome for metabolites of Phase I drug metabolism?
They can be more active, less active, or equally active as the parent drug
What is the outcome for metabolites of Phase II drug metabolism?
Metabolites are less active than the parent drug
(with the exception of morphine 6-glucuronide which is a more potent analgesic than morphine)
Which reactions does Phase II metabolism involve?
conjugation reactions (addition of large water soluble molecule to a drug)
Where does Phase I drug metabolism occur?
In the smooth endoplasmic reticulum (ER) of the cell
Where does Phase II drug metabolism occur?
In the cytosol of the cell
(with the exception of glucuronidation which is localized to the smooth ER)
What are CYPs?
- a large family of drug metabolizing enzymes
- CYPs are the predominant Phase I drug metabolizing enzyme system
The majority of drug metabolism in the body is performed by which enzymes?
hepatic CYP enzymes
How do CYPs work?
CYPs oxidize drugs by inserting one atom of oxygen into the drug molecule producing water as a byproduct.
How many families of CYPs are there?
12 families with 3 accounting for the majority of drug metabolism
Malnutrition can do what to CYPs?
Decrease CYP activity as these enzymes require dietary protein, iron, folic acid and zinc for full activity.
Which CYP metabolizes the largest fraction of currently marketed drugs (approx. 50%)?
CYP3A4
List the Phase II drug metabolizing enzymes
- UDP-glucuronosyltransferases (UGTs)
- Sulfotransferases (SULTs)
- Glutathione S Transferases (GSTs)
- N-acetyltransferases (NATs)
- Thiopurine Methyltransferase (TPMT)
Where are UGTs localized and which metabolism are they part of?
They are localized in the smooth endoplasmic reticulum and are part of phase II drug metabolism.
UGTs catalyze the transfer of what?
Catalyze the transfer of a glucuronic acid (sugar) to a drug.
How many UGT enzymes are there?
19 (human) UGT enzymes
SULTS catalyze the transfer of what?
Catalyze the transfer of a sulfate group to a hydroxyl group of drugs.
SULTs is short form for what?
Sulfotransferases
UGTs is short form for what?
UDP-glucuronosyltransferases
What are SULTs?
cytosolic phase II drug metabolizing enzymes
Glucuronidated drugs are what?
more polar and therefore more easily excreted (UGT)
Sulfated drugs are what?
more polar and therefore more easily excreted (SULTs)
How many human SULT enzymes are there?
11
What is GSTs short form for?
Glutathione S Transferases
What are GSTs?
They are phase II drug metabolizing enzymes that may be cytosolic or microsomal.
What do GSTs catalyze the transfer of?
catalyze the transfer of a glutathione molecule to a drug
How many human GST enzymes are there?
20
