Listen here: https://idiotspodcasting.buzzsprout.com/1782416/episodes/14842295-77-pk-illuminating-elimination
Elimination = Metabolism + Excretion
- Definition: Processes that irreversibly remove a drug from the body
- The ‘Drug out’ part of pharmacokinetics.
- Metabolism of the drug determines how the drug is excreted.
- Not all drugs are metabolised before excretion (’excreted unchanged’).
- Elimination starts as soon as drug first enters the liver. It is an ongoing process that does not ‘wait’ until the drug has finished distributing equally throughout the body
Metabolism
- Definition: Chemical conversion of a drug into a form amenable to excretion.
- This is achieved through 2 main ways: Phase I & II reactions
| Phase |
Chemical reactions |
Effect |
| I |
Oxidation/Reduction |
|
| Hydrolysis |
Introduce/unmask polar groups on drug |
|
| (-OH or -NH2). |
|
|
| II |
Conjugation |
Addition of polar groups to drug: |
- Glucuronate (glucuronidation)
- Glutathione (Glutathione conjugation)
- Glycine (Glycine conjugation)
- Sulphate (Sulphation)
- Acetyl (Acetylation)
- Methyl (Methylation) |
- These reactions enhance the drug’s ionic charge, which makes them easier to excrete.
- This is essential for lipophilic drugs, which will otherwise simply diffuse back across the renal cell membranes, then back into the plasma.NB: These reactions are responsible for the ‘First-Pass metabolism’ discussed in ‘Blethering about Bioavailability’.
- The main sites of metabolism are liver, kidneys & lung, but these enzymes are present at various levels in most tissues.
- Note that not all drugs undergo both phases: e.g. some drugs undergo Phase II directly, depending if they already possess -OH, -NH or COOH groups.
Phase I: Cytochrome P450 Enzymes
- Definition: A large family of >50 hepatic enzymes that primarily oxidise drugs.
- Site: mostly on hepatocyte endoplasmic reticulum.
- They are responsible for most Phase I metabolism.