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.
