Predicting interactions

Last updated: Friday, July 08, 2016

It is not always easy to find information to show with a reasonable degree of certainty that an interaction does or does not occur. If you can’t find any specific information, you may be able to predict whether an interaction is likely or unlikely, using these points as a guide:

  1. How are the two medicines cleared from the body? Are they metabolised by the same enzyme? Is one of the drugs known to inhibit or induce it? The SPC will often help you with this kind of information.

  2. Is there any information on how pairs of related drugs behave when given together? Stockley's Drug Interactions may assist you with this.

  3. Do the two drugs have any frequent side effects in common? These effects may be additive when the two drugs are given together. Again the SPC may be valuable here.

Interactions involving cytochrome p450


Portrayal of the structure of CYP3A4  
Courtesy of www.ebi.ac.uk
Cytochrome p450 is a very large family of related enzymes; each individual one is called an isoenzyme. The isoenzymes are named using an agreed method of nomenclature involving numbers and letters of the alphabet. 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)

A knowledge of which isoenzyme metabolises a particular drug can make understanding of interactions easier. Individual drugs are not metabolised exclusively by one isoenzyme, but one usually predominates. Theophylline, for example, is metabolised by CYP1A1, 1A2, 2D6 and 2E1, but 1A2 is the main one. 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. 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 need to look up whether a drug is an inducer, inhibitor or substrate of cytochrome p450, then the Transformer website is very helpful: just type in the name of the medicine you're interested in and it will tell you about any involvement with cytochrome p450.

Note that while some enzyme inhibitors or inducers affect the isoenzymes responsible for their own metabolism (e.g. ciclosporin), others can affect completely different isoenzymes or are hardly metabolised at all (e.g. ciprofloxacin).