PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs.Cytochrome P450 enzymes - Introduction.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Cytochrome P450 enzymes - Introduction

Cytochrome P450 enzymes - Introduction

Introduction

These notes are intended to be comprehensive as far as psychotropic drugs are concerned; so do please email me at www.psychotropical.com if you note any significant omissions or if you have any comments or questions. Information about non-psychotropic drugs is also included, especially commonly used general medical drugs.

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

  1. They metabolise most of the drugs we use (by oxidative, reductive or hydrolytic modification to a more water-soluble form-- for renal excretion).
  2. The varying 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.
  3. There is great genetic isoform variation for almost all 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 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 will come in soon; regulatory authorities are already giving more weight to this aspect of things when considering approvals.
  6. Drugs and xenobiotics (ie 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, the endogenous substrates of most of them are presently unknown. All P450 enzymes are similar in structure and mechanism of action. 3A4 is the most abundant in the human liver and is known to metabolise the majority of drugs whose biotransformation is presently known.

This large family of enzymes are classified with numbers and letters as below based on their degree of structural similarity. This is now precisely known; the genetic sequence of all of them has been worked out and the frequencies of the varients in various population and ethnic groups is becoming better documented. eg see below, 2C19 poor metaboliser status is very common in people of asian descent.

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

  • 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 CYP450:-- 1A2, 2D6, 2C9 / 19 and 3A4. (see text of other notes for details about each one).

Genetic polymorphism

Most of them (1A2, 1A6, 2D6, 2C9, 2C19 and 3A4) are highly genetically polymorphic, ie have several / many isoforms. Isoforms may have very 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 fetus, 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 varying levels of the drug in the system.

For instance: the incidence of poor 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.

CYP2D6 metabolises, in part or in whole, the tricyclic psychotropics -- that includes antihistamines, neuroleptics and tricyclic antidepressants, and various other drugs. CYP2D6 is potently blocked by fluoxetine, paroxetine, quinidine and ritnavir; which may 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 and citalopram are the safest bet. The other three selective serotonin reuptake inhibitors, fluvoxamine, fluoxetine and paroxetine all have potentially problematic cytochrome P450 interactions and are best avoided as much as possible by those not fully conversant with the latest data concerning interactions.

Fluvoxamine, especially, is so potent as a cytochrome P450 enzyme inhibitor that it is best eschewed by anyone not fully conversant with all possible interactions.

Induction

Some P450s 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-metabolizing enzymes, such as cytochrome P450s and specific transferases. 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:-- "CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance suggest that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation".

A recent paper evaluated a cocktail of caffeine, omeprazole, dextromethorphan, and midazolam for simultaneous phenotyping of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase. The results indicated no pharmacokinetic or pharmacodynamic interactions that would limit the use of this mixture for phenotyping these cytochrome P450 enzymes.

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. Genotyping for cytochrome P450 enzymes may avoid some of these deaths.

Administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5 to 10. (Fluvoxamine showed a concentration-dependent inhibition of clozapine N-demethylation. It inhibited activity of all five cytochrome P450 (CYP) isoforms previously implicated in the demethylation of clozapine:-1A2 with high affinity of Ki 0.041 and 2C19 at 0.087 microM. Ki for CYP2C9 was 2.2 and 2D6 4.9 microM (Ki for CY3A4 was 24 microM).)