Interactions: Cytochrome p450
A basic knowledge of cytochrome p450 enzymes helps to understand many drug interactions. It is actually a large family of enzymes, and each individual one is called an isoenzyme. The isoenzymes are named using numbers and letters, and the four most commonly involved in metabolising drugs are:| CYP1A2 (e.g. clozapine, theophylline) | CYP2C9 (e.g. phenytoin, warfarin) |
| CYP2D6 (e.g. fluoxetine, tamoxifen) | CYP3A4 (e.g. ciclosporin, carbamazepine) |
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| Structure of CP3A4 Courtesy of www.ebi.ac.uk |
Medicines that make an isoenzyme more active are called inducers. This means that drugs inducing CYP1A2 (e.g. tobacco) will speed up the main route of theophylline metabolism resulting in a shorter duration of action and lower peak plasma concentrations. This may reduce efficacy.
Medicines that make an isoenzyme less active are called inhibitors. Drugs which inhibit CYP1A2 (e.g. ciprofloxacin) will slow theophylline metabolism, giving a longer half-life and higher peak levels. This may cause toxicity.
When you need to look up whether a drug is an inducer, inhibitor or substrate of cytochrome p450, then the relevant SmPC is usually helpful.
Quick clinical question
When checking an interaction, you discover that rifampicin induces the metabolism of warfarin via CYP 3A4. What will this mean for a patient's INR? ➔ Consider, then click for answer.
When checking an interaction, you discover that rifampicin induces the metabolism of warfarin via CYP 3A4. What will this mean for a patient's INR? ➔ Consider, then click for answer.
Inducers speed up metabolism so warfarin will be less active and the INR will therefore be reduced.
Note that while some enzyme inhibiting or inducing medicines affect the isoenzymes responsible for their own metabolism (e.g. ciclosporin), others can affect completely different isoenzymes or are themselves hardly metabolised at all (e.g. ciprofloxacin).
Note that some enzyme inhibitors do so reversibly (e.g. fluconazole) so the inhibition wears off as quickly as the offending drug is eliminated. Others have an irreversible action (e.g. erythromycin) so reversal has to wait for the offending drug to be eliminated and for new enzyme to be synthesised.
Induction and inhibition: when it starts and when it ends
How long do these enzyme effects take to begin, and what happens if the drug that causes them is stopped? This is a common question and Stockley's Drug Interactions explains it well:
'The timing and extent of enzyme induction depends on the half-life of the inducing drug, its dose and the rate of turnover of the enzyme being induced. Therefore, broadly speaking, it can take days or even 2 to 3 weeks to develop fully, and might persist for a similar length of time when the enzyme inducer is stopped. This means that enzyme induction interactions can be delayed in onset and slow to resolve...
'More common than enzyme induction is enzyme inhibition. This results in the reduced metabolism of an affected drug, so that it might begin to accumulate within the body, the effect usually being essentially the same as when the dose is increased. Unlike enzyme induction, which can take several days or even weeks to develop fully, enzyme inhibition can occur rapidly, often within 2 to 3 days, resulting in the rapid development of toxicity; however, the effects might not be maximal until the inhibiting drug reaches steady-state. The faster onset of enzyme inhibition is because this process often involves the drug binding with the enzyme, thereby preventing its function, whereas enzyme induction requires increased synthesis of the enzyme (a slower process).'
'More common than enzyme induction is enzyme inhibition. This results in the reduced metabolism of an affected drug, so that it might begin to accumulate within the body, the effect usually being essentially the same as when the dose is increased. Unlike enzyme induction, which can take several days or even weeks to develop fully, enzyme inhibition can occur rapidly, often within 2 to 3 days, resulting in the rapid development of toxicity; however, the effects might not be maximal until the inhibiting drug reaches steady-state. The faster onset of enzyme inhibition is because this process often involves the drug binding with the enzyme, thereby preventing its function, whereas enzyme induction requires increased synthesis of the enzyme (a slower process).'
Claire L Preston (editor), Stockley's Drug Interactions [online], London: Pharmaceutical Press www.medicinescomplete.com/mc/stockley/current/ (accessed on 14/10/2024).
This quote reproduced by kind permission.