Pharmacology 2060A/B Lecture Notes - Lecture 4: Warfarin, Sulfotransferase, Malnutrition

24 views5 pages
Pharmacokinetics- Metabolism
Drug Metabolism
Metabolism is the enzyme mediated alteration of a drugs structure
Metabolism is also referred to as biotransformation
Sites of drug metabolism include:
oLiver- primary site of drug metabolism
oIntestine- enterocytes that line the gut are able to metabolize drugs
oStomach- a site for the metabolism of alcohol
oKidney- underappreciated as a metabolic organ
oIntestinal bacteria- normal bacterial flora play an important role in drug metabolism
Why do we need drug metabolism?
Important in humans to protect us from a number of environmental toxins as well as synthesize essential
endogenous molecules
A summary of common exogenous toxins that drug metabolism protects us from are summarized below.
Similarly, essential endogenous molecules synthesized by drug metabolizing enzymes are shown
Note that even things like vegetables considered to be healthy would be toxic if we didn’t have enzymes to
process them!
Therapeutic Consequences of Drug Metabolism
Drug metabolism can have several different consequences
Therapeutic consequences of drug metabolism:
1. Increase water solubility of drugs to promote their excretion (lipophilic  hydrophilic)
2. Inactive drugs (active  inactive)
3. Increase drug effectiveness (active  more active)
4. Activate prodrugs (inactive until metabolized) (prodrug  active)
5. Increase drug toxicity (non-toxic  toxic)
Kinetics of Drug Metabolism
First Order
In most clinical situations the concentration of drug is much lower than the metabolic capacity of the body.
In these situations, drug metabolism displays 1st order kinetics
In 1st order kinetics, the rate of drug metabolism is directly proportional to the concentration of free drug
This means a constant fraction of drug is metabolized per unit time
Figure shows an example of 1st order metabolism. The top panel shows how the plasma concentration
changes over time. Notice how the concentration decreases faster when there are higher drug
concentrations than at the end when the drug concentrations are low. The bottom panel shows the amount
of drug and the amount of enzyme. Notice how there is much more enzyme then there is drug. This is
typical in drugs that display first order metabolism
find more resources at oneclass.com
find more resources at oneclass.com
Unlock document

This preview shows pages 1-2 of the document.
Unlock all 5 pages and 3 million more documents.

Already have an account? Log in
Zero Order
In zero order kinetics, the plasma drug concentration is much higher than the metabolic capacity of the
body
Drug metabolism is constant over time
This means a constant amount of drug is metabolized per unit time
One of the best examples of zero order kinetics is ethanol
The figure to the right shows an example of zero order metabolism. The top panel shows how the
plasma concentration changes over time. Notice how a constant amount of drug is eliminated over
time. This means that the metabolism is independent of drug concentration. The bottom panel shows
the amount of drug and the amount of enzyme. Notice this time how there is much more drug than
there is enzyme. This is typical in drugs that display zero order metabolism
First Pass Metabolism
PO drugs (oral) may undergo significant metabolism prior to entering the systemic circulation
1st pass metabolism can occur via:
1. Hepatocytes in the liver
2. Intestinal enterocytes
3. Stomach
4. Intestinal bacteria
The result is a decreased amount of parent drug that enters systemic circulation
Extraction Ratio
The amount of metabolism on the first pass through the liver can greatly determine a drug’s bioavailability
Drugs are characterized as having high or low extraction ratio (ER) depending on how much metabolism
occurs on the first pass through the liver
High ER = highly metabolized through first pass through liver, low bioavailability
High ER Drugs Low ER Drugs
Have low oral bioavailability (1-20%) High high oral bioavailability ( > 80%). PO doses are usually similar to
IV doses
PO doses are usually much higher than IV doses (to
compensate for high first pass metabolism)
Small changes in hepatic enzyme activity have little effect on
bioavailability
Small changes in hepatic enzyme activity produce large
changes in bioavailability
Not very susceptible to drug-drug interactions
Very susceptible to drug-drug interactions Take many passes through the liver via the systemic circulation before
they are completely metabolized
find more resources at oneclass.com
find more resources at oneclass.com
Unlock document

This preview shows pages 1-2 of the document.
Unlock all 5 pages and 3 million more documents.

Already have an account? Log in

Get access

Grade+
$10 USD/m
Billed $120 USD annually
Homework Help
Class Notes
Textbook Notes
40 Verified Answers
Study Guides
1 Booster Class
Class+
$8 USD/m
Billed $96 USD annually
Homework Help
Class Notes
Textbook Notes
30 Verified Answers
Study Guides
1 Booster Class