Bilal Padhi

Cytochrome P450 (CYP450) are a group of enzymes encoded by the P450 genes and responsible for the metabolism of most drugs seen in clinical practice.

90% of drugs are metabolised by CYP3A5, CYP3A4, CYP2D6, CYP2C19, CYP2C9 and CYP1A2. CYP3A4 and CYP2D6 are the most significant enzymes.1

Polymorphism is the genetic mutations that give rise to enzymes with different abilities to metabolise drugs. These genetic variabilities are responsible for the inter-individual variability in therapeutic response and toxicity to all major classes of drugs given at the standard dose.

The expression of CYP450 enzymes varies between populations and will greatly influence drug metabolism and response.

For example, CYP2D6 polymorphisms are expressed in four different phenotypes:

Poor metabolisers are characterised by the inability to metabolise drugs via the CYP2D6 metabolic pathway, resulting in an increased risk of adverse effects and toxicity. PM phenotype affects up to 10% of Caucasians and 30% of the Chinese population.2,3

At the other extreme, ultrarapid metabolisers metabolise the drug rapidly, resulting in a lack of therapeutic response in these individuals.

However, the reverse applies to prodrugs (drugs that are converted to their active forms in the body). Poor metabolisers fail to convert the prodrug into its active form leading to a lack of therapeutic response. In contrast, ultrarapid metabolisers rapidly convert the prodrug to its active form, causing potential toxicity.

Ultrarapid metaboliser phenotypes are most prevalent in the North African, Ethiopian and Arab populations, affecting 16% – 28% of the populations. In the rest of the world, the prevalence of ultrarapid metaboliser phenotypes is estimated to be 1% in the Chinese, Japanese and Hispanic populations and 5.5% in Western Europe.3,4

Intermediate metabolisers have a reduced metabolism capacity compared to extensive metabolisers (who are classified as “normal”), therefore are more susceptible to adverse effects.

For example, nortriptyline is a common tricyclic antidepressant and a substrate of CYP2D6. In intermediate metabolisers, the metabolism of nortriptyline is reduced as compared to extensive metabolisers. As a result, the higher plasma concentration of nortriptyline in intermediate metabolisers increases the risk of potential side effects. A dose reduction should be considered in these patients.

Enzyme substrates are drugs or other substances that bind to and are metabolised by the CYP450 enzymes

Examples of CYP450 substrates include:

Inducers increase the expression level of CYP450 enzymes resulting in increased metabolism of drugs and subsequently reducing the therapeutic concentration.

Therefore, potential changes in drug concentration may cause treatment failure. The effects usually develop over several days and may be slow to resolve depending on the half-life of the inducer.

Examples of CYP450 inducers include:

Inhibitors prevent the CYP450 enzymes from working or reduce the rate of an enzyme-catalysed reaction. Consequently, this decreases drug metabolism in the body and increases the potential for toxicity. The effect often occurs quickly and is dose related.

Examples of CYP450 inhibitors include::

Clinical Pharmacist

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