Pharmacology 2060A/B Lecture Notes - Lecture 4: Prodrug, Active Metabolite, Biotransformation
15 May 2018
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Module 4 – Pharmacokinetics – Metabolism
4.1 - Drug metabolism
- Metabolism is the enzyme mediated alteratio of a drug’s struture
- Metabolism is also referred to as biotransformation
- Sites of drug metabolism include:
o Liver: primary site of metabolism
o Intestine: enterocytes that line the gut are able to metabolize drugs
o Stomach: sit for the metabolism of alcohol
o Kidney: often thought of as an organ for excretion – underappreciation as a metabolic
organ and contains many drug metabolizing enzymes
o Intestinal bacteria: normal bacterial flora play an important role in drug metabolism
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
- Exogenous toxins that drug metabolism protects us from exogenous toxins
o Exogenous: things we put in our body that are not naturally there to begin with
o Exogenous agents have the potential to be toxins but our body has drug metabolizing
enzymes to prevent the toxicity
- Endogenous processes:
o Same family of enzymes that are responsible for metabolizing drugs are also crucial for
endogenously regulated processes
o Essential endogenous molecules are synthesized by drug metabolizing enzymes
- Note that even things like egetales osidered to e health ould toi if e did’t hae
enzymes to process them!
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Therapeutic consequences of drug metabolism
- Drug metabolism can have several different consequences
- 1) Increase water solubility of drugs to promote their excretion
o Lipophilic → Hydrophilic
o Most drugs are fat-soluble and if there is no drug metabolism, they may never be
eliminated in the body
o Most important consequence: increase water solubility of drugs to allow them to be
excreted
- 2) Inactivate drugs
o Active drug with activity → Inactive drug
o Metabolite does not have activity
- 3) Increase drug effectiveness
o Active → More active
o Metabolism may make the drug more active
o E.g. metabolites of morphine: analgesic used to relieve pain
- 4) Activate prodrugs (prodrugs are inactive until metabolized)
o Prodrug (inactive) → Active drug
o Prodrugs: drugs that have no pharmacological activity until they are metabolized to an
active metabolite
- 5) Increase drug toxicity
o Non-toxic → Toxic
o Takes a drug that is not toxic and metabolizes it to a drug that exhibits toxicity
4.2 - Kinetics of drug metabolism
First order
- Most drugs in clinical use exhibit first order kinetics
- 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
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- First order kinetics = there is more drug metabolizing enzymes than drugs
- Rate of drug metabolism is directly proportional to the concentration of free drug
o This means a constant fraction of drug is metabolized per unit time
- Graph shows an example of 1 st order metabolism
o Shows how plasma concentration changes over time
o When the concentration is high, the rate of metabolism is also very high
o When the drug concentration is low, the rate of metabolism is very low
o Concentration decreases faster when there are higher drug concentrations than at the
end when the drug concentrations are low
Zero order
- In zero order kinetics, the plasma drug concentration is much higher than the metabolic capacity
of the body
o There is much more drug than there is enzyme
- In zero order kinetics drug metabolism is constant over time.
o This means a constant amount of drug is metabolized per unit time.
o Rate of drug metabolism does not change over time
o Drug metabolism is the same for high and low drug concentrations
- One of the best examples of zero order kinetics is ethanol/alcohol
- Graph shows how the plasma concentration changes over time.
o A constant amount of drug is eliminated over time.
o This means that the metabolism is independent of drug concentration.
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
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