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Many drugs are metabolised by the cytochrome P-450 (CYP450) enzymes in the liver. The end result is either inactive
compounds that can be excreted, or active compounds which can be further metabolised leading to eventual removal from
the body. The CYP450 system consists of many enzyme subtypes each metabolising a specific range of drugs (substrates).
Some of the enzymes (e.g. CYP2D6 and CYP2C19) exhibit genetic polymorphisms and the frequency of these polymorphisms
varies between ethnic groups. These genetic differences mean some people have an enzyme with reduced or no activity. In
the case of CYP2D6 there are at least 3 variants giving phenotypes who are poor metabolisers, extensive metabolisers (the
majority of people) or ultra fast metabolisers.
People who are poor metabolisers may have an increased risk of adverse reactions to a drug metabolised by the affected
enzyme or reduced capability to convert a parent drug into the active drug. As an example of genetic variation, the frequency
of CYP2D6 poor metabolisers is 5-10% in Caucasians and 1% in East Asians.
Some CYPs (CYP3A4) can have their activity increased (induced) by other drugs leading to increased substrate metabolism.
Conversely some drugs can block (inhibit) the activity of a CYP enzyme and reduce substrate metabolism.
- Fluoxetine is a substrate for CYP2D6 and a potent inhibitor of this enzyme. TCAs such as amitriptyline are also
metabolised by CYP2D6. Fluoxetine will inhibit this and increase plasma concentrations of the TCA and increase dose
related adverse effects.
- The activity of codeine is mainly due to conversion to morphine by CYP2D6. A poor metaboliser for this enzyme will
have poor analgesic response due to lack of conversion. A drug which is an inhibitor of CYP2D6 (e.g. paroxetine) will,
in effect, change a normal metaboliser to a poor metaboliser.
- A CYP2D6 poor metaboliser will have reduced capacity to metabolise some antidepressants (e.g. fluoxetine, paroxetine
and amitriptyline) and be more sensitive to dose related adverse effects.
- Theophylline is a substrate for CYP3A4. Phenytoin induces CYP3A4 which increases the metabolism of theophylline
and reduces plasma concentrations.
Many antidepressant and psychoactive drugs are metabolised by CYP2D6, and to a lesser extent, CYP2C19 which exhibit
genetic polymorphism (see Table 1).
Table 1. Main metabolic pathways of commonly prescribed antidepressants
||Main Metabolising enzyme
||CYP2D6 Some other CYPs involved
||Potent inhibitor of CYP2D6
Active metabolite (norfluoxetine) inhibits CYP3A4
||Potent inhibitor of CYP2D6
CYP2D6 only partly involved
|Only inhibits CYP2D6 very weakly
||CYP2D6 inhibitors taken at same time will increase plasma concentrations of venlafaxine. Active metabolite
is metabolised by CYP3A4
|Most TCA’s (e.g. amitriptyline)
Some other CYPs involved
|CYP2D6 inhibitors taken at same time will increase plasma concentrations of TCA
In general CYP2D6 poor metabolisers are likely to have poor tolerance to TCAs, venlafaxine and the SSRIs paroxetine
or fluoxetine. A smaller dose may be required for therapeutic effect and to minimise adverse effects. Citalopram may be
better tolerated by CYP2D6 poor metabolisers. Conversely, CYP2C19 poor metabolisers are likely to have poor tolerance
of some TCAs and possibly citalopram.
Related reading and resources
De Leon J, Armstrong S, Cozza K. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing
for CYP450-2D6 and CYP450-2C19. Psychosomatics, 2006;47:75-85.
Drug Interactions; Defining genetic difference on pharmacologic responses. Available from;
Martin J, Fay M. Cytochrome P450 drug interactions: are they clinically relevant? Aust Prescr, 2001;24:10-2.