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Cytochrome P450: recent developments

By Stockley's editorial team

Better understanding of cytochrome P450 has increased our ability to predict the clinical relevance of interaction studies. The Stockley’s editorial team explains

Pharmacists will know that cytochrome P450 (CYP) is a large family of isoenzymes purported to account for about 75 per cent of drug metabolism1 but recent developments mean that it is more likely that theoretical information we have is applied to practice.

The discovery of CYP dates to the early 1950s and this family has been the subject of much research in the decades since. In 1966 there was already indirect evidence that multiple forms existed, and research during the 1970s focused on establishing this concept and identifying forms.2 By 1987 at least 65 various forms had been cloned and sequenced, and the naming system we are familiar with today was established.2,3

It was during the 1980s that the role of these multiple forms in drug interactions began to emerge. In humans, a few isoenzymes seem to be responsible for about 90 per cent of the CYP-mediated metabolism of commonly used drugs, namely (in order of importance) CYP3A4, CYP2D6, and CYP2C9, with CYP1A2, CYP2C19, and CYP2C8 also involved. CYP2B6 and CYP2E1 seem to be more minor players.

The activity of CYP isoenzymes can be influenced by other drugs, and as early as the 1950s it was discovered that drug metabolism in animal liver could be induced by other compounds.3 Isoenzyme activity might also be inhibited, and this is a more common phenomenon than induction. If the metabolism of a drug is decreased by a CYP inhibitor, the body’s exposure to it (area under the curve; AUC) is increased; and if metabolism is induced, exposure is decreased. If exposure to a drug is increased this might result in adverse effects and toxicity. See Panel 1 for some clinically important examples. Conversely, reduced exposure can potentially lead to reduced drug efficacy.

Panel 1: examples of inhibitor interactions

Simvastatin with itraconazole (potent CYP3A4 inhibitor) Concurrent use is contraindicated due to markedly increased simvastatin exposure and possibility of toxicity (myopathy or rhabdomyolysis).

Sildenafil with clarithromycin or erythromycin (potent and moderate CYP3A4 inhibitors, respectively) Sildenafil exposure is increased, with greater risk of adverse effects. Reduce the dose of sildenafil.

Tizanidine with fluvoxamine (potent CYP1A2 inhibitor) Concurrent use is contraindicated due to very markedly increased tizanidine exposure and potential hypotension and sedation. Use another selective serotonin reuptake inhibitor.

The mechanism and speed of induction and inhibition varies; at its simplest, induction requires increased synthesis of the isoenzyme and so is delayed in onset, whereas inhibition prevents functioning of the isoenzyme, often by drug binding with the isoenzyme, which is generally a faster process.
Recently the complexities of drug interactions mediated by CYP isoenzymes have become more evident as reliable data from mechanistic and pharmacokinetic studies have become available.

One important point to note is that there is no clinical evidence that the concurrent use of two drugs that are solely substrates of the same CYP isoenzyme (that is, when neither is also an inhibitor) will result in a relevant interaction by competing for metabolism by this isoenzyme, although this suggestion is sometimes included in studies or case reports to explain a possible interaction.

Evaluation now required

The various CYP isoenzymes generally metabolise a number of substrates, and many substrates are metabolised by a variety of isoenzymes. Thus, understanding which, if any, of these isoenzymes are responsible for the metabolism of a new drug and whether the drug itself is an inhibitor or inducer of any isoenzymes is important in the evaluation of its interaction potential.

This is now an integral part of the development process and last year, both the European Medicines Agency4 and the US Food and Drug Administration5 updated guidance for the pharmaceutical industry on the study of drug interactions for drugs in development.

In vitro and often also in vivo studies are necessary to elucidate the drug interaction potential of a new drug fully. In broad terms, an interaction between a drug and known inhibitors or inducers of a particular CYP pathway is considered likely  if that pathway contributes more than 25 per cent to the total clearance of the drug.6

Similarly, if a drug is principally metabolised by a single CYP isoenzyme rather than several, it is more likely that drug interactions will occur.6 For older, established drugs reliable data, particularly in vitro data, are patchy.

Mechanistic studies

In vitro studies are used to identify the isoenzyme(s) responsible for the metabolism of a drug, or to identify if a drug is an inhibitor or inducer. They should be carried out using human derived samples (eg, liver microsomes) and validated techniques. If results are positive, then in vivo studies are required to determine the sensitivity of a drug or substrate for a particular isoenzyme, and to assess the clinical relevance of any inhibition or induction. If the results are negative, in vivo studies are not necessary. Good in vitro studies are more common for newer drugs.

Clinical pharmacokinetic studies

In vivo studies are used to identify the clinical relevance of the findings from in vitro studies, or to study an interaction under controlled conditions. They should be carried out in humans, usually in healthy subjects (unless safety considerations preclude this).

Ideally studies will be crossover in design so that the same subjects receive all combinations, and should use accepted or validated substrates, inhibitors or inducers. The exposure of the drug or substrate being tested should be measured before and during use with the inhibitor or inducer when at steady state. Many other factors are important in the design of these studies but detailed discussion is outside the scope of this article.

Potency and sensitivity

Inhibitors and inducers vary in the size of their effect on CYP isoenzymes. Similarly substrates vary in their sensitivity to these isoenzymes.
Results of clinical drug interaction studies allow inhibitors or inducers and substrates to be described and classified on this basis.

Inhibitors and inducers can be described as very potent, potent, moderate, or weak, depending on their effect on the exposure of a substrate. The range of effect for inhibitors is a =10-fold increase in AUC for very potent inhibitors to between a 1.25- and two-fold increase for weak inhibitors. For inducers, the range of effect is a =90 per cent decrease in AUC for very potent inducers to between a 20 and 50 per cent decrease for weak inducers.

A substrate can be described as sensitive (with its AUC being increased five-fold or more with a potent inhibitor), moderate or minor, depending on the effect of a potent inhibitor on its exposure.A sensitive substrate can be used as a probe to assess the activity of other drugs on an isoenzyme.

Most of the major isoenzymes responsible for drug metabolism have widely accepted or validated probe substrates or potent inhibitors that are recommended for use in in vivo studies. Panel 2 lists some examples.
Inducers of CYP isoenzymes are less specific than inhibitors. Note also, that some inhibitors and inducers of CYP isoenzymes also affect drug transporter proteins such as P-glycoprotein (see PJ 2011;286:595–6).

Panel 2: probe substrates and inhibitors in studies

 Enzyme Probe substrate  Inhibitor
 CYP3A4Midazolam (oral)Ketoconazole
 CYP2D6 DextromethorphanParoxetine
 CYP2C9Tolbutamide
None known
 CYP1A2Caffeine
Fluvoxamine
 CYP2C19Omeprazole
Fluvoxamine
 CYP2C8 Repaglinide
Gemfibrozil

Genetic polymorphism

Greater understanding in genetics has led to the discovery that some CYP isoenzymes are subject to genetic variation, which means that some of the population have a variant gene for a certain isoenzyme, resulting in important differences in its drug metabolising capacity.

An individual with a gene variation that results in little or no activity of an isoenzyme is described as a poor metaboliser, whereas an individual with no gene variations and hence normal isoenzyme activity is described as an extensive metaboliser. The isoenzymes known to exhibit such polymorphism are CYP2D6, CYP2C9, and CYP2C19.

There are great variations among different ethnic groups and when studying drug interactions this can be an important issue to take into consideration. If an individual is a poor metaboliser for a particular isoenzyme the effect of a potent inhibitor of that isoenzyme will be minimal but if he or she is an extensive metaboliser, the same scenario would lead to increased exposure to a sensitive substrate.

For a polymorphic isoenzyme, comparison of drug exposure in poor metabolisers versus extensive metabolisers in a clinical pharmacokinetic study is an acceptable alternative to studying the effects of a potent inhibitor of that isoenzyme. Currently, however, determining the metaboliser status of an individual is a research tool rather than a clinical one.

Application to practice

The increased understanding of CYP isoenzymes and their involvement in interactions has led to better designed studies and an increased ability to predict the clinical relevance of the findings. Because of this, the results of these types of studies (described above) are often now included in manufacturers’ product literature.

‘Stockley’s drug interactions’ has a large focus on such data and evaluates these from original published studies and product literature to provide clinical interpretation and guidance about application to practice. Stockley’s is now adopting a classification system for substrates, inhibitors and inducers of CYP isoenzymes (based on that included in the guidance documents for the pharmaceutical industry from the EMA and FDA), along with standard terminology.

This allows extrapolations and more reliable predictions relating to similarly metabolised drugs or similarly potent inhibitors or inducers to be made, and advice regarding dose adjustments, monitoring, or selection of non-interacting alternatives.

Pharmacists and other healthcare professionals will, therefore, be better informed to make decisions for patient management, and may also be better able to interpret clinical pharmacokinetic studies involving CYP substrates, inhibitors or inducers and, apply the findings to their own practice.

Key points

  • Evaluating a new drug’s interaction potential is now an integral part of drug development. Results from studies describing interactions are now often included in product literature.
  • Extrapolating data can help us predict the clinical relevance of trial findings related to drug interactions.
  • Inhibition of cytochrome P450 is more common than induction. It can lead to increased drug exposure and adverse effects. Very potent inhibitors can result in a 10-fold or greater increase in exposure.
  • Inhibition often occurs via drug binding with the isoenzyme so is generally faster than induction, which requires increased synthesis of the isoenzyme and so is delayed in onset.
  • An interaction between a drug and known inhibitors or inducers of a particular cytochrome P450 pathway is considered likely  if that pathway contributes more than 25 per cent to the total clearance of the drug.
  • Determining the metaboliser status of an individual (ie, genetics) is currently a research tool rather than a clinical one.

 

About the authors

This article has been produced by Julia Sawyer, Rhoda Lee, Claire L. Preston and Elizabeth Foan on behalf of the “Stockley’s drug interactions” editorial team.  ‘Stockley’s drug interactions’ is available in print through Pharmaceutical Press (www.pharmpress.com) or electronically with quarterly updates through MedicinesComplete (www.medicinescomplete.com).

References

1.    Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol (2008) 21, 70–83.~18052394~
2.    Porter TD. Jud Coon: 35 years of P450 research, a synopsis of P450 history. Drug Metab Dispos (2004) 32, 1–6.~14709613~
3.    Omura T. Recollection of the early years of the research on cytochrome P450. Proc Jpn Acad Ser B Phys Biol Sci (2011) 87, 617–40.~22156409~
4.    European Medicines Agency. Guideline on the investigation of drug interactions. 21 June 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf (accessed 10/06/13).
5.    US Food and Drug Administration. Guidance for industry. Drug interaction studies – study design, data analysis, implications for dosing and labeling recommendations. Draft guidance, February 2012. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf (accessed 10/06/13).
6.    Zhang L, Zhang Y, Zhao P, Huang S-M. Predicting drug-drug interactions: an FDA perspective. The AAPS J (2009) 11, 300–6.~19418230~

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11127907

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Supplementary images

  • As early as the 1950s it was discovered that drug metabolism could be increased by other compounds (cytochrome p450-erythromycin complex; LAGUNA DESIGN/SCIENCE PHOTO LIBRARY)

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