Pharmacology
Drug Metabolism – ADME basics 2
1. Learning outcomes
Explain the requirement for metabolism to remove lipophilic drugs
Describe how the balance of Phase I and II metabolism affects:
- the duration of a therapeutic window for a drug
- how the two phases interact to aid removal of drugs
Integrate the knowledge above to explain how metabolism often lead to activation and then
deactivation of drugs, considering:
- Implications for toxicity
- Implications for efficacy
Describe the main routes of excretion and apply reasoning as to why a particular route is utilised.
Link and explain the role of excretion on drug action, predicting how this and other factors can
be modified to improve patient response.
2. The fate of a drug
3. Why do we metabolise drugs
The body naturally acts to remove chemical (endogenous or exogenous)
Main routes of removal are urine and faeces (i.e. hydrophilic / polar)
Most drugs are lipophilic / non-polar
Must be made hydrophilic / polar before they can be excreted
Metabolism is the process of converting chemicals to more polar metabolites
Primarily in liver, but can occur in all organs
4. Drug metabolism overview
Drug can either be hydrophilic
already and be excreted in the
faeces or it can have a small
reactive group added to it. Going
down the phases it becomes
conjugate and that’s our
hydrophilic product. There are
some drugs that may have to go
through phase I to be activated
, Pharmacology
Drug Metabolism – ADME basics 2
5. Phase I Metabolism
Functionalisation reactions, NADPH found in TCA cycle and O2 is always in the body
Create or reveal a ‘handle’ for Phase 2 metabolism
- Oxidation
- Reduction
- Hydrolysis
Oxidation the most important
- Catalysed by a super-family of enzymes called the Cytochrome P450s
6. Cytochrome P450s
Present in species from bacteria to mammals: 57 known human P450s
Many P450s are inducible by compounds that are substrates, when it binds to drug it can bind its
own expression (happens the same when a drug goes through a transporter!)
For drug metabolism, families 1-3 are the most important
- CYP1: Polycyclic Aromatic Hydrocarbons (PAHs)
- CYP2: Many drugs,
- CYP3: >50% of drugs in clinical use that are oxidised
Remember CYPs have endogenous substrates as well!
To be in the family they need to have 70% sequence similarity and to be in the subfamily 40%
similarity in aa
7. CYP3A4 – an example Phase I enzyme
Most abundant P450 in human liver
>50% of drugs in clinical usage today, that are oxidised, are substrates
Very wide substrate specificity
Drug Metabolism – ADME basics 2
1. Learning outcomes
Explain the requirement for metabolism to remove lipophilic drugs
Describe how the balance of Phase I and II metabolism affects:
- the duration of a therapeutic window for a drug
- how the two phases interact to aid removal of drugs
Integrate the knowledge above to explain how metabolism often lead to activation and then
deactivation of drugs, considering:
- Implications for toxicity
- Implications for efficacy
Describe the main routes of excretion and apply reasoning as to why a particular route is utilised.
Link and explain the role of excretion on drug action, predicting how this and other factors can
be modified to improve patient response.
2. The fate of a drug
3. Why do we metabolise drugs
The body naturally acts to remove chemical (endogenous or exogenous)
Main routes of removal are urine and faeces (i.e. hydrophilic / polar)
Most drugs are lipophilic / non-polar
Must be made hydrophilic / polar before they can be excreted
Metabolism is the process of converting chemicals to more polar metabolites
Primarily in liver, but can occur in all organs
4. Drug metabolism overview
Drug can either be hydrophilic
already and be excreted in the
faeces or it can have a small
reactive group added to it. Going
down the phases it becomes
conjugate and that’s our
hydrophilic product. There are
some drugs that may have to go
through phase I to be activated
, Pharmacology
Drug Metabolism – ADME basics 2
5. Phase I Metabolism
Functionalisation reactions, NADPH found in TCA cycle and O2 is always in the body
Create or reveal a ‘handle’ for Phase 2 metabolism
- Oxidation
- Reduction
- Hydrolysis
Oxidation the most important
- Catalysed by a super-family of enzymes called the Cytochrome P450s
6. Cytochrome P450s
Present in species from bacteria to mammals: 57 known human P450s
Many P450s are inducible by compounds that are substrates, when it binds to drug it can bind its
own expression (happens the same when a drug goes through a transporter!)
For drug metabolism, families 1-3 are the most important
- CYP1: Polycyclic Aromatic Hydrocarbons (PAHs)
- CYP2: Many drugs,
- CYP3: >50% of drugs in clinical use that are oxidised
Remember CYPs have endogenous substrates as well!
To be in the family they need to have 70% sequence similarity and to be in the subfamily 40%
similarity in aa
7. CYP3A4 – an example Phase I enzyme
Most abundant P450 in human liver
>50% of drugs in clinical usage today, that are oxidised, are substrates
Very wide substrate specificity
