02.03.2 Phase I

The first phase of metabolism is Phase I. Phase I reactions involve common chemical reactions such as oxidation (interaction with an oxygen), reduction (interaction with a hydrogen), and hydrolysis (interacting with water).

The liver has a huge number of metabolising enzymes. The best characterised metabolic pathways are those catalysed by cytochromes, which are haem proteins. The Cytochrome P450 system (CYP) is a superfamily of distinct enzymes, known as CYP1, 2 and 3, with more than 50 haem-containing enzymes identified to date. The CYPs are found in the endoplasmic reticulum of the liver cell.

One of the most important of the CYPs for drug metabolism is CYP3A4. In this nomenclature for CYP3A4, 3 is for the family of enzyme, A for the subfamily, and 4 is the enzyme isoform (Figure 2.4).

Figure 2.4 Cytochrome P450 families, sub-families and isoforms: CYP3A4 (Copyright QUT University, Sheila Doggrell)

The classification of CYP enzymes into families, subfamilies and isoforms is based on the similarities of the genes encoding for them. CYP3A4 is the most abundantly expressed, and is involved in the metabolism of about 50% of clinically used drugs. CYP2D6 and CYP2C8/9 are also commonly involved in drug metabolism. Drug interactions often occur at the level of these metabolising enzymes, and will be discussed in more detail in the section on drug interactions. The levels of these enzymes are subject to induction and inhibition, and the activity of the enzymes may vary with a subject’s genetic makeup (see Chapter 11).