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DTB | Nalmefene for alcohol dependence
DTB CME/CPD*
Is there more to learn about cytochrome P450 enzymes? The cytochrome P450 system is a group of enzymes, found mainly in the liver and gut mucosa, that plays a crucial role in controlling the concentrations of many endogenous substances and drugs.1 The activity of the individual enzymes can vary over time and from person to person in response to diet, medicines or exposure to environmental pollutants. It has been almost 15 years since DTB reviewed the significance of the cytochrome P450 system and its relevance to prescribing (Why bother about cytochrome p450 enzymes?).1 A lot has changed in healthcare over that time, but has our understanding of this important aspect of drug metabolism altered significantly? Here we provide a brief overview of the function of cytochrome P450 enzymes and look at some of the concepts that have become established, or have begun to emerge, since the publication of our previous article.
* DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, subscribers must sign into DTB with their username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. The answers to the multiple choice questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
dtb.bmj.com
Background Drugs are metabolised by a number of different enzyme systems, the most important of which is cytochrome P450 (CYP), a very large family of related isoenzymes (see Box 1).2 Although many families and subfamilies of the enzymes exist, only a few specific subfamilies seem to be responsible for most (about 90%) of the metabolism of commonly used
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DTB | Is there more to learn about cytochrome P450 enzymes?
drugs. The most important isoenzyme is CYP3A4, followed by CYP2D6 and CYP2C9. In addition, CYP1A2, CYP2C8 and CYP2C19 are also significant. Fewer drugs are known to be metabolised by CYP2B6 and CYP2E1. The main biochemical effect of CYP isoenzymes is to catalyse oxidation, which usually makes the metabolised drug (substrate) more watersoluble and so more readily excreted by the kidneys. Oxidation will also alter the substrate’s biological activity, usually decreasing it (as happens, e.g. with corticosteroids), but sometimes converting it into an active form (e.g. the prodrug clopidogrel).1,3 Drugs can act as inducers or inhibitors of these isoenzymes and thereby increase or decrease the metabolism of other drugs, leading to drug interactions. The onset and duration of an interaction are dependent on the mechanism involved: • Enzyme induction requires increased synthesis of the enzyme.4 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. As a result, enzyme induction may take days or even 2–3 weeks to develop fully, and might persist for a similar length of time when the inducing drug is stopped. This means that enzyme induction interactions can be delayed in onset and slow to resolve.4 • Enzyme inhibition tends to be of faster onset (often within 2–3 days) because the process generally involves the drug binding with the enzyme, thereby preventing its function. Although toxicity may develop rapidly, the effects might not be maximal until the inhibiting drug reaches steady-state.4
Box 1: Cytochrome P450 (CYP) enzyme classification1 CYP enzymes have been subdivided into families and subfamilies according to the similarity of their amino acid structure. Isoenzymes with greater than 40% sequence similarity are grouped in families denoted by CYP (representing cytochrome P450) followed by a number (e.g. CYP2). Isoenzymes within a family that have greater than 55% sequence similarity are grouped in a subfamily designated by a capital letter (e.g. groups of isoenzymes in the CYP2 family are called CYP2C, CYP2D, CYP2E). Individual isoenzymes that have been specifically identified are given a further number (e.g. CYP2D6). Although there is overlap, each CYP isoenzyme tends to metabolise a discrete range of substrates.
Understanding drug interactions The ability to predict when interactions might occur is very much more important than retrospectively finding out why two drugs interact.4 When knowledge of CYP was in its infancy, predicting drug interactions was more of an art than a science, but as understanding has developed, finer distinctions have become possible. Rather than simply classifying drugs as CYP3A4 inducers, inhibitors and substrates, it is possible to quantify the magnitude of the effect of an inducer or inhibitor on a substrate (as weak, moderate or potent) and the specificity of a substrate for a particular isoenzyme (as minor, moderate or sensitive). For example, atorvastatin and simvastatin are substrates of CYP3A4;5 however, simvastatin tends to exhibit more profound interactions when given with CYP3A4 inhibitors. This is because simvastatin exhibits a higher specificity for CYP3A4 and is a sensitive substrate for this isoenzyme, whereas atorvastatin has less specificity and therefore its metabolism is less affected by inhibition of this isoenzyme.6,7 The practical importance of this is illustrated by their interactions with the moderate CYP3A4 inhibitor, diltiazem. Diltiazem increases the exposure to
58
atorvastatin by 51%8 and to simvastatin by 480%.9 The effect on atorvastatin is slight, and the company indicates considering the use of a lower maximum dose,8 whereas the effect on simvastatin is moderate to severe and therefore a lower maximum simvastatin dose of 20mg daily is strongly advised.10 This illustrates the benefit of being able to quantify the potency of any inhibition (or induction), but it is important to understand the basis on which such classifications are made. A universally accepted classification is still evolving, but definitions based on guidance for the pharmaceutical industry issued by the European Medicines Agency11 and the US Food and Drug Administration,12 and on pharmacokinetic data have been more widely adopted. The clinical relevance of the inhibition of a particular isoenzyme by a drug is determined in a clinical pharmacokinetic study using a drug that is known to be metabolised exclusively or almost exclusively through metabolism by the isoenzyme being studied (probe substrate).11 Among other characteristics, the ideal probe substrate needs to be specific for the isoenzyme in question, unaffected by drug transporters (endogenous substances that act as carriers across biological membranes),4 and available in oral and intravenous forms.13 The classification is then based on the extent of the increase in exposure or decrease in clearance of the probe substrate.11 Likewise, for inducers, the classification is based on the extent of the decrease in exposure or increase in clearance of the probe substrate. 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 in healthy adults to produce reliable results that can be applied to clinical practice (see Table).11,12 Table: Examples of probe substrates and inhibitors used during in vivo drug interaction studies11,12 CYP isoenzyme
Probe substrate
Accepted inhibitor
CYP1A2
Caffeine
Fluvoxamine
CYP2D6
Dextromethorphan
Paroxetine
CYP2C8
Repaglinide
Gemfibrozil
CYP2C9
Tolbutamide
None known
CYP2C19
Omeprazole
Fluvoxamine
CYP3A4
Midazolam (oral)
Ketoconazole
CYP, cytochrome P450.
Once the relevant in vivo studies have been conducted, the results can be used to make predictions about the way other similarly studied and classified drugs might behave. When a new drug comes on to the market, its interaction potential may only have been studied with one potent CYP3A4 inhibitor (e.g. ketoconazole), but it is possible to predict with a greater degree of certainty that the new drug will behave similarly with other potent CYP3A4 inhibitors (such as itraconazole, clarithromycin and a number of ritonavir-boosted HIV-protease inhibitors).11 Predictions based on this type of study are appearing more commonly in the Summary of Product Characteristics (SPCs), and as one classification becomes universally adopted, there should be much more consistency across various SPCs in the range of potential drug interactions identified.
P-glycoprotein and CYP3A4
Although the role of CYP in drug interactions has been investigated for many years, it is now better understood that numerous other factors might alter the expected outcome of an interaction. For example, there is a large overlap between the activity of inhibitors, inducers and substrates of CYP3A4 and of the drug transporter protein, P-glycoprotein (see Box 2);12,14 in fact, P-glycoprotein, or P-glycoprotein in conjunction
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DTB | Is there more to learn about cytochrome P450 enzymes?
with CYP3A4, might be involved in many of the drug interactions previously thought to be due to effects on CYP3A4 alone.
Box 2: P-glycoprotein P-glycoprotein is the most well-known transporter involved in drug interactions. It promotes the transport of substances, including drugs, across cell membranes, expelling the substances from the cells (efflux). P-glycoprotein is found in many body systems including the cells lining the intestines, where it can pump drugs back into the gut lumen thereby decreasing their absorption, and in the endothelial cells of the blood-brain barrier where it can reduce the exposure of the brain to certain drugs.4
For example, diltiazem and verapamil are moderate inhibitors of CYP3A4 and would therefore generally be expected to have a similar effect on substrates of this isoenzyme.12 However, verapamil has a significantly greater effect on the exposure to sirolimus, a CYP3A4 substrate, than diltiazem (220% and 60% respectively).15,16 Sirolimus is also a substrate of P-glycoprotein16 and the difference could relate to differences in P-glycoprotein inhibition by diltiazem4 and verapamil.17 There is evidence that P-glycoprotein and CYP3A4 operate in a coordinated way and, in the intestine particularly, P-glycoprotein might influence the extent to which CYP3A4 substrates are metabolised by CYP3A4 in the intestinal wall. The resultant effect depends on the ability of the drug to inhibit or induce both P-glycoprotein and CYP3A4 in the liver and intestinal wall. However, the overall effect is more complex and possibly dependant on factors such as the timing of drug administration (simultaneous versus separate administration) and the duration over which the drugs are given (single versus multiple doses of drugs).4 As a result, the exact nature of the interplay between these two systems and its involvement in drug interactions is not yet clear, and is the subject of much research. However, it does seem that the relative affinities of drugs for CYP3A4 or P-glycoprotein, and the relative size of the individual effects of each system, ultimately dictates the resulting net effect of interactions involving dual CYP3A4 and P-glycoprotein substrates, inhibitors and inducers.
Pharmacogenomics and cytochrome P450
Variation in the genes of some individuals from those in the rest of the population is known as genetic polymorphism. One manifestation of genetic polymorphism is that some patients are either lacking in, or have less effective, CYP isoenzymes, altering their capacity to metabolise drugs that are substrates of the isoenzyme in question. This can be an important consideration when assessing drug interactions.18 The best known example of an isoenzyme subject to genetic polymorphism is CYP2D6, for which a small proportion of the population have a variant with little or no activity (caused by the presence of two non-functional alleles in the CYP2D6 gene). Such individuals are described as poor metabolisers (or as possessing the poor metaboliser phenotype), and make up about 5–10% of Caucasians.19 Individuals with normal enzyme activity (resulting from the presence of 1 or 2 alleles with normal function in the gene) are described as extensive metabolisers (70–80% of Caucasians). In addition, for CYP2D6, it is now known that
there are ultra-rapid metabolisers who have more than one extra functional gene (around 3–5% of Caucasians) and also intermediate metabolisers who usually have one non-functional and another with reduced function (10–17% of Caucasians). The metaboliser status (or phenotype) of any given individual is genetically determined and distribution varies greatly among ethnic groups, resulting in variable percentages within a given population.
Clinical relevance This alteration in expression of CYP isoenzymes may explain why some patients develop drug interactions and others do not. For example, normally the pharmacokinetic interaction between warfarin and omeprazole is minor and does not result in a relevant increase in the anticoagulant effect of warfarin.4,20 Despite this, a patient previously stabilised on warfarin developed a prolonged bleeding time and haematuria after being given omeprazole.21 Although further research would be required to establish the theory, it seems possible that only CYP2C19 poor metabolisers, who have 5 to 10-fold higher levels of omeprazole, may experience a significant interaction with warfarin. It seems likely that, with the increasing knowledge of pharmacogenetics, more cases like this will be reported, and it may be possible to identify subgroups of patients most at risk of drug interactions. However, it is important to remember that while genetic polymorphism may influence the outcome of drug therapy, it is only one of many factors that can influence the overall outcome of a drug interaction in a particular patient. Much more study is needed to truly establish the relevance of this developing field to drug interactions.
Alteration of cytochrome P450 activity by disease
It had generally been thought that therapeutic proteins such as monoclonal antibodies were unlikely to cause drug interactions by affecting CYP, principally because they are not metabolised by this system.22 However, evidence is emerging that some inflammatory diseases can alter the activity of these isoenzymes, and controlling the inflammatory processes involved with such diseases with a monoclonal antibody may have an impact on drug treatment. There are currently few published examples that support this idea, but one relatively recent study does demonstrate the potential impact of monoclonal antibody therapy. This small study investigated the effect of tocilizumab on simvastatin pharmacokinetics in 12 patients with rheumatoid arthritis.23 The study showed that simvastatin exposure was significantly reduced 1 week and 5 weeks after an intravenous infusion of tocilizumab 10mg/kg compared with simvastatin alone (simvastatin area under the plasma concentration-time curve [AUC] 43%, 90% CI 34% to 55% and 61%, 90% CI 47% to 78% respectively) resulting in levels approaching those reported in healthy people. Simvastatin is a surrogate marker for CYP3A4 activity and the results suggest that CYP3A4 activity down-regulated by inflammatory mediators in rheumatoid arthritis was normalised by administration of tocilizumab. This is an evolving area of research and more needs to be understood about how best to study this type of interaction as the usual in vitro testing processes are not suitable.22 As use of these types of treatments increase, the number of examples is likely to grow.
Conclusion Over the last 15 years, the understanding of the nature of drug interactions mediated by cytochrome P450 isoenzymes (CYP) has become more detailed, allowing better designed studies to be carried out and more accurate predictions to be made on the effects likely to be seen in clinical
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DTB | Is there more to learn about cytochrome P450 enzymes?
practice. Information sources such as the Summary of Product Characteristics and specialist resources such as Stockley’s Drug Interactions provide information on potentially serious interactions. However, as the field of pharmacogenomics develops it is likely that our understanding will grow further. Nevertheless, the emergence of knowledge of the effects mediated by novel therapeutic substances, such as the monoclonal antibodies, illustrates that there is still very much more to understand about CYP-mediated drug interactions. Clinicians need to bear such factors in mind when patients experience unexpected treatment failure or unaccounted for effects.
[R=randomised controlled trial; M=meta-analysis]
1. Why bother about cytochrome p450 enzymes? DTB 2000; 38: 93-6.
2. Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 2002; 3: 561-97.
3. Plavix 75mg tablets. Summary of product characteristics, EU. Sanofi Clir SNC, January 2014.
4. Baxter K, Preston CL (Eds). Stockley’s Drug Interactions. Tenth edition. London: Pharmaceutical Press, 2012.
5. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 2006; 112: 71-105.
R 6. Kantola T et al. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58-65. R
7. Neuvonen PJ et al. Simvastatin but not pravastatin is very susceptible to interaction with CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332-41.
8. Lipitor. Summary of product characteristics, UK. Pfizer Ireland Pharmaceuticals, August 2013.
9. Mousa O et al. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267-74.
10. Medicines and Healthcare products Regulatory Agency. Simvastatin: updated advice on drug interactions—updated contraindications. Drug Safety Update 2012; 6: S1 [online]. Available: http://www.mhra.gov.uk/Safetyinformation/ DrugSafetyUpdate/CON180637 [Accessed 23 April 2014].
11. European Medicines Agency, 2010. Guideline on the investigation of drug interactions. Draft [online]. Available: http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2010/05/WC500090112.pdf [Accessed 23 April 2014].
12. Food and Drug Administration, 2012. Guidance for industry. Drug interaction studies—study design, data analysis, implications for dosing, and labelling
Editor in Chief: James Cave OBE FRCGP Deputy Editor: David Phizackerley Managing Editor: Paul Weller Publisher: Allison Lang Marketing Executive: Rachel Mill Project Management: Laura Stephenson, Varsha Mistry, David Morrison, Alan Thomas, Katrina Sparrow Production Editor: Malcolm Smith Contributing Editors: Anna Sayburn, Sophie Ramsey, Lilian Anekwe, Grant Stewart Scientific Editors: Tannaz Aliabadi-Zadeh, Chei Hung, Sam Love, Adam Mitchell, Martin O’Brien, Irene Chiwele, Scott Ewan Clinical Editors: Kathleen Dryburgh, Sheila Feit, Julie Costello, Caroline Blaine
recommendations. Draft guidance [online]. Available: http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM292362.pdf [Accessed 23 April 2014].
13. Foti RS et al. Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos 2010; 38: 981-7.
14. Zhang L et al. Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. Mol Pharm 2009; 6: 1766-74.
R 15. Böttiger Y et al. Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers. Clin Pharmacol Ther 2001; 69: 32-40. 16. Rapamune. Summary of product characteristics, EU. Pfizer Limited, August 2013.
17. Verschraagen M et al. P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacol Res 1999; 40: 301-6.
18. Lee LS et al. Evaluation of inhibitory drug interactions during drug development: genetic polymorphisms must be considered. Clin Pharmacol Ther 2005; 78: 1-6.
19. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part 1. Clin Pharmacokinet 2009; 48: 689-723.
R 20. Uno T et al. The role of cytochrome P2C19 in R-warfarin pharmacokinetics and its interaction with omeprazole. Ther Drug Monit 2008; 30: 276-81.
21. Ahmad S. Omeprazole-warfarin interaction. South Med J 1991; 84: 674-5.
22. Lee JI et al. CYP-mediated therapeutic protein-drug interactions. Clin Pharmacokinet 2010; 49: 295-310.
23. Schmitt C et al. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther 2011; 89: 735-40.
DOI: 10.1136/dtb.2013.5.0255
Editorial Board: Paul Caldwell MB BS, MRCGP, general practitioner; Jamie Coleman MB ChB, MA, MD, MRCP, University of Birmingham; Jo Congleton MA, MD, MRCP, Worthing General Hospital; Martin Duerden B Med Sci, DRCOG, MRCGP, Dip Ther, DPH, Bangor University; David Erskine FRPharmS, Guy’s Hospital, London; Joanna Girling MB BS, MA, MRCP, FRCOG, West Middlesex University Hospital NHS Trust, London; Sean Kelly MB ChB, MD, FRCP, York Hospital; Teck Khong MB ChB, St George’s, University of London; Monica Lakhanpaul MB ChB, MD MRCP, FRCPCH, UCL Institute of Child Health, London; Donal O’Donoghue BSc, MB ChB, FRCP, Salford Royal NHS Foundation Trust; Mike Wilcock MRPharmS, Royal Cornwall Hospitals NHS Trust. Editorial correspondence: DTB, BMJ Group, BMA House, Tavistock Square, London WC1H 9JR, UK Email: [email protected] Website: www.dtb.bmj.com
Copyright © 2014 BMJ Publishing Group Ltd (“BMJ Group”). All rights reserved. Material published in DTB may not be used in any form of advertising, sales or publicity, nor be reproduced without written permission. DTB is commissioned, researched and published by BMJ Group, BMA House, Tavistock Square London WC1H 9JR, UK. Printed by Buxton Press Ltd, Buxton, Derbyshire. Disclaimer: DTB is owned and published by BMJ Group, a wholly owned subsidiary of the British Medical Association. The owner grants editorial freedom to the Editor of the DTB. DTB follows guidelines on editorial independence produced by the World Association of Medical Editors and the code on good publication practice of the Committee on Publication Ethics. DTB is intended for medical professionals and is provided without warranty, express or implied. To the fullest extent permitted by law, the BMJ Group shall not be liable for any loss, injury or damage resulting from the use of DTB or any information in it whether based on contract, tort or otherwise. Readers are advised to verify any information they choose to rely on. Changes of addresses and subscription/distribution enquiries: All changes of address and orders to DTB, Customer Service, BMJ Group, BMA House, Tavistock Square, London WC1H 9JR, UK. Tel: +44(0)20 7383 6270. Fax: +44(0)20 7383 6402. E-mail: [email protected]
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DTB | Nalmefene for alcohol dependence
DTB CME/CPD*
Is there more to learn about cytochrome P450 enzymes? The cytochrome P450 system is a group of enzymes, found mainly in the liver and gut mucosa, that plays a crucial role in controlling the concentrations of many endogenous substances and drugs.1 The activity of the individual enzymes can vary over time and from person to person in response to diet, medicines or exposure to environmental pollutants. It has been almost 15 years since DTB reviewed the significance of the cytochrome P450 system and its relevance to prescribing (Why bother about cytochrome p450 enzymes?).1 A lot has changed in healthcare over that time, but has our understanding of this important aspect of drug metabolism altered significantly? Here we provide a brief overview of the function of cytochrome P450 enzymes and look at some of the concepts that have become established, or have begun to emerge, since the publication of our previous article.
* DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, subscribers must sign into DTB with their username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. The answers to the multiple choice questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
dtb.bmj.com
Background Drugs are metabolised by a number of different enzyme systems, the most important of which is cytochrome P450 (CYP), a very large family of related isoenzymes (see Box 1).2 Although many families and subfamilies of the enzymes exist, only a few specific subfamilies seem to be responsible for most (about 90%) of the metabolism of commonly used
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DTB | Is there more to learn about cytochrome P450 enzymes?
drugs. The most important isoenzyme is CYP3A4, followed by CYP2D6 and CYP2C9. In addition, CYP1A2, CYP2C8 and CYP2C19 are also significant. Fewer drugs are known to be metabolised by CYP2B6 and CYP2E1. The main biochemical effect of CYP isoenzymes is to catalyse oxidation, which usually makes the metabolised drug (substrate) more watersoluble and so more readily excreted by the kidneys. Oxidation will also alter the substrate’s biological activity, usually decreasing it (as happens, e.g. with corticosteroids), but sometimes converting it into an active form (e.g. the prodrug clopidogrel).1,3 Drugs can act as inducers or inhibitors of these isoenzymes and thereby increase or decrease the metabolism of other drugs, leading to drug interactions. The onset and duration of an interaction are dependent on the mechanism involved: • Enzyme induction requires increased synthesis of the enzyme.4 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. As a result, enzyme induction may take days or even 2–3 weeks to develop fully, and might persist for a similar length of time when the inducing drug is stopped. This means that enzyme induction interactions can be delayed in onset and slow to resolve.4 • Enzyme inhibition tends to be of faster onset (often within 2–3 days) because the process generally involves the drug binding with the enzyme, thereby preventing its function. Although toxicity may develop rapidly, the effects might not be maximal until the inhibiting drug reaches steady-state.4
Box 1: Cytochrome P450 (CYP) enzyme classification1 CYP enzymes have been subdivided into families and subfamilies according to the similarity of their amino acid structure. Isoenzymes with greater than 40% sequence similarity are grouped in families denoted by CYP (representing cytochrome P450) followed by a number (e.g. CYP2). Isoenzymes within a family that have greater than 55% sequence similarity are grouped in a subfamily designated by a capital letter (e.g. groups of isoenzymes in the CYP2 family are called CYP2C, CYP2D, CYP2E). Individual isoenzymes that have been specifically identified are given a further number (e.g. CYP2D6). Although there is overlap, each CYP isoenzyme tends to metabolise a discrete range of substrates.
Understanding drug interactions The ability to predict when interactions might occur is very much more important than retrospectively finding out why two drugs interact.4 When knowledge of CYP was in its infancy, predicting drug interactions was more of an art than a science, but as understanding has developed, finer distinctions have become possible. Rather than simply classifying drugs as CYP3A4 inducers, inhibitors and substrates, it is possible to quantify the magnitude of the effect of an inducer or inhibitor on a substrate (as weak, moderate or potent) and the specificity of a substrate for a particular isoenzyme (as minor, moderate or sensitive). For example, atorvastatin and simvastatin are substrates of CYP3A4;5 however, simvastatin tends to exhibit more profound interactions when given with CYP3A4 inhibitors. This is because simvastatin exhibits a higher specificity for CYP3A4 and is a sensitive substrate for this isoenzyme, whereas atorvastatin has less specificity and therefore its metabolism is less affected by inhibition of this isoenzyme.6,7 The practical importance of this is illustrated by their interactions with the moderate CYP3A4 inhibitor, diltiazem. Diltiazem increases the exposure to
58
atorvastatin by 51%8 and to simvastatin by 480%.9 The effect on atorvastatin is slight, and the company indicates considering the use of a lower maximum dose,8 whereas the effect on simvastatin is moderate to severe and therefore a lower maximum simvastatin dose of 20mg daily is strongly advised.10 This illustrates the benefit of being able to quantify the potency of any inhibition (or induction), but it is important to understand the basis on which such classifications are made. A universally accepted classification is still evolving, but definitions based on guidance for the pharmaceutical industry issued by the European Medicines Agency11 and the US Food and Drug Administration,12 and on pharmacokinetic data have been more widely adopted. The clinical relevance of the inhibition of a particular isoenzyme by a drug is determined in a clinical pharmacokinetic study using a drug that is known to be metabolised exclusively or almost exclusively through metabolism by the isoenzyme being studied (probe substrate).11 Among other characteristics, the ideal probe substrate needs to be specific for the isoenzyme in question, unaffected by drug transporters (endogenous substances that act as carriers across biological membranes),4 and available in oral and intravenous forms.13 The classification is then based on the extent of the increase in exposure or decrease in clearance of the probe substrate.11 Likewise, for inducers, the classification is based on the extent of the decrease in exposure or increase in clearance of the probe substrate. 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 in healthy adults to produce reliable results that can be applied to clinical practice (see Table).11,12 Table: Examples of probe substrates and inhibitors used during in vivo drug interaction studies11,12 CYP isoenzyme
Probe substrate
Accepted inhibitor
CYP1A2
Caffeine
Fluvoxamine
CYP2D6
Dextromethorphan
Paroxetine
CYP2C8
Repaglinide
Gemfibrozil
CYP2C9
Tolbutamide
None known
CYP2C19
Omeprazole
Fluvoxamine
CYP3A4
Midazolam (oral)
Ketoconazole
CYP, cytochrome P450.
Once the relevant in vivo studies have been conducted, the results can be used to make predictions about the way other similarly studied and classified drugs might behave. When a new drug comes on to the market, its interaction potential may only have been studied with one potent CYP3A4 inhibitor (e.g. ketoconazole), but it is possible to predict with a greater degree of certainty that the new drug will behave similarly with other potent CYP3A4 inhibitors (such as itraconazole, clarithromycin and a number of ritonavir-boosted HIV-protease inhibitors).11 Predictions based on this type of study are appearing more commonly in the Summary of Product Characteristics (SPCs), and as one classification becomes universally adopted, there should be much more consistency across various SPCs in the range of potential drug interactions identified.
P-glycoprotein and CYP3A4
Although the role of CYP in drug interactions has been investigated for many years, it is now better understood that numerous other factors might alter the expected outcome of an interaction. For example, there is a large overlap between the activity of inhibitors, inducers and substrates of CYP3A4 and of the drug transporter protein, P-glycoprotein (see Box 2);12,14 in fact, P-glycoprotein, or P-glycoprotein in conjunction
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DTB | Is there more to learn about cytochrome P450 enzymes?
with CYP3A4, might be involved in many of the drug interactions previously thought to be due to effects on CYP3A4 alone.
Box 2: P-glycoprotein P-glycoprotein is the most well-known transporter involved in drug interactions. It promotes the transport of substances, including drugs, across cell membranes, expelling the substances from the cells (efflux). P-glycoprotein is found in many body systems including the cells lining the intestines, where it can pump drugs back into the gut lumen thereby decreasing their absorption, and in the endothelial cells of the blood-brain barrier where it can reduce the exposure of the brain to certain drugs.4
For example, diltiazem and verapamil are moderate inhibitors of CYP3A4 and would therefore generally be expected to have a similar effect on substrates of this isoenzyme.12 However, verapamil has a significantly greater effect on the exposure to sirolimus, a CYP3A4 substrate, than diltiazem (220% and 60% respectively).15,16 Sirolimus is also a substrate of P-glycoprotein16 and the difference could relate to differences in P-glycoprotein inhibition by diltiazem4 and verapamil.17 There is evidence that P-glycoprotein and CYP3A4 operate in a coordinated way and, in the intestine particularly, P-glycoprotein might influence the extent to which CYP3A4 substrates are metabolised by CYP3A4 in the intestinal wall. The resultant effect depends on the ability of the drug to inhibit or induce both P-glycoprotein and CYP3A4 in the liver and intestinal wall. However, the overall effect is more complex and possibly dependant on factors such as the timing of drug administration (simultaneous versus separate administration) and the duration over which the drugs are given (single versus multiple doses of drugs).4 As a result, the exact nature of the interplay between these two systems and its involvement in drug interactions is not yet clear, and is the subject of much research. However, it does seem that the relative affinities of drugs for CYP3A4 or P-glycoprotein, and the relative size of the individual effects of each system, ultimately dictates the resulting net effect of interactions involving dual CYP3A4 and P-glycoprotein substrates, inhibitors and inducers.
Pharmacogenomics and cytochrome P450
Variation in the genes of some individuals from those in the rest of the population is known as genetic polymorphism. One manifestation of genetic polymorphism is that some patients are either lacking in, or have less effective, CYP isoenzymes, altering their capacity to metabolise drugs that are substrates of the isoenzyme in question. This can be an important consideration when assessing drug interactions.18 The best known example of an isoenzyme subject to genetic polymorphism is CYP2D6, for which a small proportion of the population have a variant with little or no activity (caused by the presence of two non-functional alleles in the CYP2D6 gene). Such individuals are described as poor metabolisers (or as possessing the poor metaboliser phenotype), and make up about 5–10% of Caucasians.19 Individuals with normal enzyme activity (resulting from the presence of 1 or 2 alleles with normal function in the gene) are described as extensive metabolisers (70–80% of Caucasians). In addition, for CYP2D6, it is now known that
there are ultra-rapid metabolisers who have more than one extra functional gene (around 3–5% of Caucasians) and also intermediate metabolisers who usually have one non-functional and another with reduced function (10–17% of Caucasians). The metaboliser status (or phenotype) of any given individual is genetically determined and distribution varies greatly among ethnic groups, resulting in variable percentages within a given population.
Clinical relevance This alteration in expression of CYP isoenzymes may explain why some patients develop drug interactions and others do not. For example, normally the pharmacokinetic interaction between warfarin and omeprazole is minor and does not result in a relevant increase in the anticoagulant effect of warfarin.4,20 Despite this, a patient previously stabilised on warfarin developed a prolonged bleeding time and haematuria after being given omeprazole.21 Although further research would be required to establish the theory, it seems possible that only CYP2C19 poor metabolisers, who have 5 to 10-fold higher levels of omeprazole, may experience a significant interaction with warfarin. It seems likely that, with the increasing knowledge of pharmacogenetics, more cases like this will be reported, and it may be possible to identify subgroups of patients most at risk of drug interactions. However, it is important to remember that while genetic polymorphism may influence the outcome of drug therapy, it is only one of many factors that can influence the overall outcome of a drug interaction in a particular patient. Much more study is needed to truly establish the relevance of this developing field to drug interactions.
Alteration of cytochrome P450 activity by disease
It had generally been thought that therapeutic proteins such as monoclonal antibodies were unlikely to cause drug interactions by affecting CYP, principally because they are not metabolised by this system.22 However, evidence is emerging that some inflammatory diseases can alter the activity of these isoenzymes, and controlling the inflammatory processes involved with such diseases with a monoclonal antibody may have an impact on drug treatment. There are currently few published examples that support this idea, but one relatively recent study does demonstrate the potential impact of monoclonal antibody therapy. This small study investigated the effect of tocilizumab on simvastatin pharmacokinetics in 12 patients with rheumatoid arthritis.23 The study showed that simvastatin exposure was significantly reduced 1 week and 5 weeks after an intravenous infusion of tocilizumab 10mg/kg compared with simvastatin alone (simvastatin area under the plasma concentration-time curve [AUC] 43%, 90% CI 34% to 55% and 61%, 90% CI 47% to 78% respectively) resulting in levels approaching those reported in healthy people. Simvastatin is a surrogate marker for CYP3A4 activity and the results suggest that CYP3A4 activity down-regulated by inflammatory mediators in rheumatoid arthritis was normalised by administration of tocilizumab. This is an evolving area of research and more needs to be understood about how best to study this type of interaction as the usual in vitro testing processes are not suitable.22 As use of these types of treatments increase, the number of examples is likely to grow.
Conclusion Over the last 15 years, the understanding of the nature of drug interactions mediated by cytochrome P450 isoenzymes (CYP) has become more detailed, allowing better designed studies to be carried out and more accurate predictions to be made on the effects likely to be seen in clinical
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DTB | Is there more to learn about cytochrome P450 enzymes?
practice. Information sources such as the Summary of Product Characteristics and specialist resources such as Stockley’s Drug Interactions provide information on potentially serious interactions. However, as the field of pharmacogenomics develops it is likely that our understanding will grow further. Nevertheless, the emergence of knowledge of the effects mediated by novel therapeutic substances, such as the monoclonal antibodies, illustrates that there is still very much more to understand about CYP-mediated drug interactions. Clinicians need to bear such factors in mind when patients experience unexpected treatment failure or unaccounted for effects.
[R=randomised controlled trial; M=meta-analysis]
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Editor in Chief: James Cave OBE FRCGP Deputy Editor: David Phizackerley Managing Editor: Paul Weller Publisher: Allison Lang Marketing Executive: Rachel Mill Project Management: Laura Stephenson, Varsha Mistry, David Morrison, Alan Thomas, Katrina Sparrow Production Editor: Malcolm Smith Contributing Editors: Anna Sayburn, Sophie Ramsey, Lilian Anekwe, Grant Stewart Scientific Editors: Tannaz Aliabadi-Zadeh, Chei Hung, Sam Love, Adam Mitchell, Martin O’Brien, Irene Chiwele, Scott Ewan Clinical Editors: Kathleen Dryburgh, Sheila Feit, Julie Costello, Caroline Blaine
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DOI: 10.1136/dtb.2013.5.0255
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