5. Drug Metabolism Flashcards
Why do we need drug metabolism?
- Drugs tend to be lipophilic
- These must be metabolised to become more water soluble (polar) for easy excretion
- Metabolism tends to eliminate or reduce the pharmacological and toxicological activity
What is first pass metabolism?
- Metabolic conversion of drug before it enters the general circulation
- Hepatic - effect on the drug the first time it passes through the liver
- Pre-hepatic - intestines, stomach, oesophagus and buccal cavity have a small metabolic capacity
Why is extensive metabolism unfavourable?
- When a drug is administered and taken into the liver, it can be converted into an inactive form
- You want it to be released into the systemic circulation in a pharmacologically active form
- Extensive metabolism - less active drug in systemic circulation - low bioavailability
How can the problem of a drug that undergoes extensive first pass metabolism be overcome?
IV
Describe Phase I metabolic reactions
- Primarily in the liver
- About releasing/making functional groups
- 3 types
- Oxidation and reduction creates new functional groups
- Hydrolysis unmasks functional groups
- These functional groups serve as a point of attachment for phase II reactions
- Phase I reactions often inactivate drugs but can also activate drugs (prodrugs - inactive => active)
- Little change in polarity
- If a drug was lipophilic it will still be pretty lipophilic
How are Phase II metabolic reactions different to Phase I?
• More complicated
• Bigger polar groups added to the molecule
• Conjugate formed is almost always inactive
• Molecule becomes more polar and less lipid soluble so that it can be excreted
• Includes acetylation, sulphation, methylation etc.
• Drugs can undergo only Phase II sometimes, Phase I or neither
• For enzyme name: reaction + transferase
e.g. acetylation => acetyl transferase, sulphation => sulphotransferase
Outline the main enzyme system in the liver?
- Cytochrome P450
- 57 enzymes involved in this system
- Capability to metabolise loads of xenobiotics (most drugs)
- Main system in Phase I oxidising reactions
- Also involved in metabolism of endogenous compounds e.g. steroids
- Several isozymes involved (same function, different structure)
What is the basic reaction of CYP450?
RH (drug) + NADPH (reducing agent) + O2 + H+ (source of protons can be from any aqueous environment)
=>
ROH (oxidised drug) + NADP+ + H2O
Describe how CYP450 works?
1) Drug binds to catalytic iron (Fe3+) at centre of P450’s catalytic site (porphyrin ring also present in active site)
2) Electron donated by NADPH
3) Electron picked up by P450 complex and Fe3+ => Fe2+
4) Molecular oxygen binds to catalytic site too
5) Fe2+ becomes Fe3+ as it loses electron to O2 which becomes unstable
6) Second electron from NADPH converts Fe3+ => Fe2+ AGAIN
7) Fe2+ donates electron to oxygen AGAIN to become Fe3+ - oxygen is now very unstable
8) Drug converted into hydroxylated derivative - reactive oxygen cleaved and becomes water by picking up 2 protons
9) Drug (ROH) released and P450 returns to cycle with Fe3+ ready to undergo next cycle
What happens when an aliphatic pentobarbitone is hydroxylated?
- OH added to penultimate CH of functional group
* Pharmacological activity removed
What happens when (aromatic) acetanilide is hydroxylated?
- OH added to carbon ring
* Paracetamol is the hydroxylated derivative (Phase I - prodrug => active drug)
What is N-demethylation and what happens to imipramine when this is done to it?
- Oxidation of a methyl in a nitrogen environment (carbon on a nitrogen)
- Common: 80-90% of drugs have amine functions
- Very effective way of removing pharmacological activity
- Imipramine has a tertiary amine structure
- Methyl group on nitrogen is metabolised and leaves as formaldehyde
What is O-demethylation and give an example of a drug involved in this reaction
- Oxidation of a methyl on an oxygen by P450
- Oxygen converted to hydroxyl group
- Formaldehyde released
- e.g. codeine => morphine
What is N-oxidation?
• Oxidation of the nitrogen group itself
• Amine oxide produced
• Nitrogen is trivalent - 2 lone electrons
• Electrons not normally used - but can be donated (to oxygen) to make a dative bond
• Catalysed by Flavin containing monooxygenase
- works similarly to P450 but has a different catalytic site
Describe the deficiency of the enzyme involved in N-oxidation
- Flavin containing monooxygenase deficiency
- Trimethylamine is a smelly chemical humans produce in the GIT
- FCMO converts trimethylamine => trimethylamine N-oxide (odourless and polar - readily excreted)
- Defective FCMO - trimethylamine can’t be metabolised
- Sweated and breathed out - fish odour syndrome
