Interactions: Cytochrome p450

Last updated: Thursday, November 23, 2017

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)
Structure of CYP3A4   courtesy of
Many, but not all, drugs are metabolised by cytochrome p450 and a knowledge of which isoenzyme is involved can make understanding of interactions easier. CYP2D6 is commonly involved, and said to be responsible for metabolising around a quarter of prescription medicines. However, individual drugs are not metabolised exclusively by one isoenzyme, although one usually predominates. Theophylline, for example, is metabolised by CYP1A1, 1A2, 2D6 and 2E1, but 1A2 is the main one. As a result, theophylline is said to be a substrate for CYP1A2.

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.
If you can’t remember the difference between inhibitor and inducer, then try memorising that inhibitors have bitten the enzyme to stop it working.
When you need to look up whether a drug is an inducer, inhibitor or substrate of cytochrome p450, then the Transformer website is helpful, although it’s a technical rather than a clinical website. Type a medicine into the Drug Name box and hit return; you get lots of technical data, but effects on cytochrome p450 are listed halfway down under ‘CYP interactions’.

Quick ward 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.
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).

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).'
Claire L Preston (editor), Stockley's Drug Interactions [online], London: Pharmaceutical Press (accessed on 20/11/2017). This quote reproduced by kind permission.
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.