It is worthwhile being aware of the fact that dissemination of information about adverse drug interactions is partly dependant on pharmaceutical companies who monopolise, directly or indirectly, many of the sources of information available to the medical profession. Some people might consider it understandable that pharmaceutical companies wish to emphasise their product’s benefits and advantages over other similar products, but not the disadvantages, such as propensity to cause interactions with other drugs.

However, doctors (and consumers) are well advised to adopt a rather more critical and objective perspective. I have commented on this issue in the literature, particularly in relation to fluoxetine (1). I criticised a paper in a leading expert review publication concerning the most recent safety data about Fluoxetine. Even after all our experience, and all the deaths associated with drug interactions in which fluoxetine has been implicated, it still failed to give the appropriate degree of prominence to these major disadvantages of the drug. The paper was authored by an employee of the company that makes the drug. It may seem tedious to keep revisiting this theme, but it serves to remind readers that the influence of drug companies on everything that you read, even in supposedly prestigious journals, is extensive and frequently seriously misleading. For a full discussion of this topic see my essay on antidepressants.

It is helpful to have knowledge of cytochrome P450 enzymes because:--

  1. They metabolise most of the drugs we use, usually to a less active, or inactive, form. This is by oxidative, reductive or hydrolytic modification to a more polar (water-soluble) form that is suitable for renal excretion.
  2. The level of their activity in individuals (as a result of different genetic isoforms) determines the speed of metabolism of a drug. That in turn influences the plasma level, efficacy and the side effects (2-11).
  3. There is great genetic isoform variation for most cytochrome P450 enzymes; both between individuals within a group (eg Caucasians) and between groups of different genetic and ethnic lineages.
  4. There are various endogenous (within the body itself) factors (eg hormones) and exogenous factors (eg other drugs and foods) that alter the level of CYP450 enzyme activity.
  5. An understanding of the topic, and the genotype of the subject and their current medication, enables quite precise predictions to be made about clinically relevant, and potentially dangerous, interactions. Genotyping prior to giving some drugs has arrived, but will be a little more complex than some observers appreciate .
  6. Drugs and xenobiotics (i.e. foreign biological molecules) with similar structures are likely to have similar substrate / inhibitor properties; so if one member of a group is known to cause problems others may too. However, small structural changes can cause large changes in particular properties.

Summary

There are more than one thousand P450 enzymes in living organisms, the endogenous substrates of many of them are presently unknown. All CYP450 enzymes are similar in structure and mechanism of action. 3A4 is the most abundant in the human liver. This large family of enzymes is classified with numbers and letters, as below, based on their degree of structural homology (similarity). This is now precisely known; the genetic sequence of all of them has been worked out and the frequencies of the variants in various population and ethnic groups is becoming more fully documented: see Human Cytochrome CYP450 (CYP) Allele Nomenclature Committee: http://www.cypalleles.ki.se/

There are about ten different Cytochrome P450 enzymes of particular importance to drug metabolism in humans:--

  • CYP 1A2 / 1A6
  • CYP 2B6
  • CYP 2C8 / 2C9 / 2C19
  • CYP 2D6
  • CYP 2E1
  • CYP 3A4

Cytochrome P450 enzymes of particular importance for psychotropic drugs are:- 1A2, 2D6, 2C9 / 19 and 3A4. (see text of other notes for details about each one). Important recent reviews and comments to consult are (2, 4, 5, 13-21) and see medicine.iupui.edu/flockhart/

Genetic polymorphism

Most of them (1A2, 1A6, 2D6, 2C9, 2C19 and 3A4) are genetically polymorphic, i.e. have several / many isoforms. Isoforms have small differences in their amino acid sequences, so slight there may be doubt about their practical relevance in some instances (eg 3A3 / 3A4). Some isoforms occur only at certain stages of development (eg 3A7 only in the foetus, it does not appear to be expressed in the adult) or only in particular tissues (eg 3A5 in the lung).

Those cytochrome P450 enzymes that are genetically polymorphic have variant isoforms of the enzymes expressed in different individuals. These may have widely varying activities for metabolising drugs. These variant isoforms metabolise drugs either faster or slower thus producing different levels of the drug, and different substrates may not always be affected to the same degree (12).

For instance: the incidence of poor (slow) metaboliser (PMs) of CYP2C19 substrates is much higher in some Asian subgroups (15% up to nearly 100%) than in Caucasians (3-6%). In the case of 2D6 it has recently been shown that some people have multiple copies of the more active form of the gene. Such people (about 1%) are 'ultra-fast' metabolisers (UMs). This helps one to appreciate that for a drug dependent on 2D6 there may be a 100-fold difference in blood levels between population extremes in a large sample. 2D6 particularly sems to be of evolutionary significance (4, 5).

CYP2D6 metabolises, in part or in whole, the tricyclic psychotropics, all those with a protonable N atom -- that includes antihistamines, neuroleptics and tricyclic antidepressants, and various other drugs. CYP2D6 is potently blocked by fluoxetine, paroxetine, quinidine and ritnavir; which will cause significant and even dangerous, interactions.

CYP450 3A4 metabolises, amongst others for instance, terfenidine, astemizole, cisapride and ergotamine. 3A4 is potently inhibited by ketoconazole, (erythro- and other) -mycins, indinavir, fluoxetine, nefazodone and grapefruit juice as well as numerous other bio-organic molecules from edible plants and 'herbal' plants.

Although this field may seem complex it is not unduly complicated. A basic understanding and a good source of data will allow confident judgements about clinical problems to be made in a majority of cases.

As is the case for most CYP450 enzyme inhibition scenarios involving selective serotonin reuptake inhibitors sertraline is the safest bet. Citalopram / escitalopram are borderline, being significant inhibitors of CYP2D6 even a minimum dose levels. The other selective serotonin reuptake inhibitors, fluvoxamine, fluoxetine and paroxetine all have problematic CYP450 interactions and are best avoided as much as possible by those not conversant with the latest data concerning interactions. Some expert opinion is that fluvoxamine and fluoxetine, and perhaps paroxetine, should not be used at all.

Induction

Some CYP450s are more subject to induction than others. These mechanism are being elucidated, eg nuclear receptors like CXR, PAR etc. Phenobarbital increases metabolic capability of hepatocytes by its ability to activate numerous genes encoding various xenochemical metabolising enzymes, such as CYP450s and specific transferase enzymes. The key nuclear receptor CAR that mediates the induction has now been identified.

Multiple pathways

Drugs may be metabolised via more than one route, and also to different metabolites (which may themselves be active and / or inactive, and with the same or differing types of activity). To know what will happen to a drug we have to consider via what route(s) it is metabolised and how it may compete with / block / induce, one (or more) other enzyme isoforms and which other drugs dependent on those may therefore be effected. It can be quite complex.

Some drugs are broken down via several different CYP450 types; a recently documented example is perphenazine where CYP1A2, 3A4, 2C19 and 2D6 were the most important.

It is useful to remember that the metabolites of many drugs, and there may be several, are frequently not known precisely, nor have their potencies for various systems that they might affect been quantified. Furthermore, any activity they might have for blocking other enzymes, or causing other forms of unexpected pharmacological effect, may be unknown.

The term substrate refers to a molecule that is susceptible to structural change facilitated by the action of an enzyme in the body. It is a kind of a lock and key mechanism where the particular complex shapes of different molecules fit particular enzymes, which facilitate the chemical change from one form into another. Most of the enzymes we are talking about facilitate the inactivation of drugs. If the quantity of a particular drug exceeds the capacity of an enzyme to process it the enzyme is said to be saturated. It is rather like a crowd of people leaving an auditorium. If too many people try to get through the doors too quickly a log jam occurs. With enzymes this means that up to a certain concentration a drug can be processed quickly and in proportion to the amount present. That results in what is technically referred to as linear phamacokinetics. That means the relationship between the drug dose and its concentration, plotted on a graph, forms a straight line. Once the enzyme is saturated by higher concentrations of the drug phamacokinetics become a non-linear, which means that the level in the system goes up more rapidly than you would expect for a given dose increase.

General consequences

The incidence of serious and fatal adverse drug reactions is high in hospital patients. This causes an estimated 100,000 deaths per year in the US, making it the 5th most frequent cause of death (22). Genotyping for CYP450 enzymes may avoid some of these deaths.

Potent inhibitors are likely to cause serious or dangerous interactions in some circumstances, especially because some of these drugs have a narrow therapeutic margin .

Of the selective serotonin reuptake inhibitor antidepressants, and the other new antidepressants to date, only fluoxetine and paroxetine are potent inhibitors of CYP450 2D6 (14, 17, 23, 24). The subjects who may experience drastic changes in blood levels are those who were previously fast metabolisers (ultrarapid metabolisers (UMs)); their levels may go from low to high when they are converted from fast to slow by fluoxetine or paroxetine. This change can be great enough to be both dangerous and fatal.

Fluoxetine is particularly problematic being a potent 2D6 inhibitor and also a inhibitor of 3A4 and 2C19. These effects can persist for weeks after cessation because of its long elimination half life.

Beta-blocker eye drops get into the systemic circulation more than is appreciated. In PMs- (poor (slow) metabolisers) this has a more marked effect. Symptoms caused by systemic effects have included decreased heart rate, depression, confusion, headache, fatigue and hallucinations.

Codeine phosphate and other codeine variants, oxycodone and hydrocodone, as wel as tramadol, are all ‘pro-drugs’, i.e. Inactive, or less active, forms that are metabolised to more active forms. This is via 2D6, hence poor metabolisers (PMs) will be substantially less susceptible to the analgesic effect because they will metabolise it to its active metabolite more slowly and therefore have lower blood levels of the more pharmacologically active component. Also patients on fluoxetine and paroxetine may fail to respond because their 2D6 is blocked, producing the same end result.

References

1. Gillman, PK, Drug interactions and fluoxetine: a commentary from a clinician?s perspective. Ex Op Drug Saf, 2005. 4: p. 965-969.

2. Ingelman-Sundberg, M, Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends in Pharmacological Sciences, 2004. 25(4): p. 193-200.

3. Ingelman-Sundberg, M, Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol, 2004. 369(1): p. 89-104.

4. Ingelman-Sundberg, M, Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. The Pharmacogenomics Journal, 2005. 5(1): p. 6-13.

5. Ingelman-Sundberg, M, The human genome project and novel aspects of cytochrome P450 research. Toxicology and Applied Pharmacology, 2005. 207(2 Suppl): p. 52-6.

6. Ingelman-Sundberg, M and Rodriguez-Antona, C, Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 2005. 360(1460): p. 1563-70.

7. Sim, SC, et al., A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clinical Pharmacology and Therapeutics, 2006. 79(1): p. 103-13.

8. Kawanishi, C, et al., Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol, 2004. 59(11): p. 803-7.

9. Bertilsson, L, Dose of proton pump inhibitors and the CYP2C19 genotype. Basic Clin Pharmacol Toxicol, 2004. 95(1): p. 1.

10. Herrlin, K, et al., Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol, 2003. 56(4): p. 415-21.

11. Christensen, M, et al., The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther, 2003. 73(6): p. 517-28.

12. Bogni, A, et al., Substrate specific metabolism by polymorphic cytochrome P450 2D6 alleles. Toxicology In Vitro, 2005. 19(5): p. 621-9.

13. Preskorn, S, Clinical Pharmacology of SSRI's. 5 - How SSRIs as a Group Are Similar. 2005.

14. Preskorn, SH, Drug-Drug Interactions: Proof of Relevance (Part I). J Psychiatr Pract, 2005. 11(2): p. 116-122.

15. Kirchheiner, J and Brockmoller, J, Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther, 2005. 77(1): p. 1-16.

16. Wedlund, PJ and de Leon, J, Cytochrome P450 2D6 and antidepressant toxicity and response: what is the evidence? Clin Pharmacol Ther, 2004. 75(5): p. 373-5.

17. Preskorn, SH, How drug-drug interactions can impact managed care. Am J Manag Care, 2004. 10(6 Suppl): p. S186-98.

18. Kirchheiner, J, et al., Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther, 2004. 76(4): p. 302-12.

19. Kirchheiner, J, et al., Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry, 2004. 9(5): p. 442-73.

20. Eap, CB, Sirot, EJ, and Baumann, P, Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies. Therapeutic Drug Monitoring, 2004. 26(2): p. 152-5.

21. Brosen, K, Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie, 2004. 59(1): p. 5-12.

22. Ingelman-Sundberg, M, Genetic susceptibility to adverse effects of drugs and environmental toxicants. The role of the CYP family of enzymes. Mutat Res, 2001. 482(1-2): p. 11-9.

23. Preskorn, SH, Debate resolved: there are differential effects of serotonin selective reuptake inhibitors on cytochrome P450 enzymes. J Psychopharmacol, 1998. 12(3): p. S89-97.

24. Preskorn, SH, Effects of antidepressants on the cytochrome P450 system. Am J Psychiatry, 1996. 153(12): p. 1655-7.