Phase I Metabolism (Allan)

Drug Metabolism – Phase I

Drug metabolism can be broken down into phase I and phase II. The phase that will be discussed here is phase I which generally involves the conversion of hydrophobic compounds to more polar compounds which are more easily excreted or more reactive to further modification which may be required for excretion(3). This further transformation for excretion is part of phase II metabolism and will not be discussed here.

The conversion of compounds to more polar compounds usually involves the addition of, or the conversion to -OH, -NH2, or –SH (McKee and McKee, 2009). The phase I reactions can be classified into several categories, oxidation involving cytochrome P450, other oxidation reactions, isomerisation, hydration, hydrolysis, reduction and other miscellaneous reactions (Gibson and Skett, 2001). A classic example of an oxidation reaction that is part of phase I metabolism is the oxidation of aspirin as shown in figure 1.


Figure 1. Oxidation of acetyl salicylic acid in phase I drug metabolism. (Rang & Dale 2007)

The acetyl group on aspirin is much less polar and reactive than the hydroxyl group that is formed after phase I metabolism. However, the salicylic acid must undergo further modification to be excreted which occurs in phase II. The formation of the hydroxyl group is important to phase II since it provides a more reactive substrate than the original acetylated compound.

As mentioned, many of the reactions involve the cytochrome p450 monooxygenase system which is found primarily in the endoplasmic reticulum of the liver. Below are a list of some of the reactions which have been modified and generalized from Gibson and Skett (2001).

Figure 2. Some examples of oxidation reactions which are catalyzed by the cytochrome p450 monooxygenase system (Gibson and Skett, 2001).

Not all the oxidations that take place in phase I drug metabolism involve the cytochrome p450 system. There are other enzymes which are involved including alcohol dehydrogenase (fig. 3) which converts alcohols to aldehydes and further oxidation of aldehydes by aldehyde dehydrogenase to carboxylic acids which are readily excreted.


Figure 3. Oxidation of an alcohol to an aldehyde via alcohol dehydrogenase as part of phase I metabolism. Modified from Gibson and Skett (2001).

Not only are oxidation reactions important but reductions play a key role in phase I drug metabolism as well. These reactions are usually catalyzed by microsomal enzymes in the liver (Gibson & Skett, 2001). Some compounds which are often metabolised in this way are those which contain nitro and azo functional groups.


Figure 4. Reduction reactions as part of phase I drug metabolism, modified from Gibson and Skett (2001).

The final type of reaction which will be discussed is hydrolysis. Esters, carbamates and hydrazides are hydrolysed by a variety of enzymes (Gibson & Skett, 2001).

Figure 5. Ester hydrolysis, reproduced from (5).

The conversion of the ester to two smaller, more polar compounds (a carboxylate ion and an alcohol) allow for much easier membrane crossing and therefore excretion.

Although many reactions that take place in phase I are part of the excretion process, some reactions act to convert a pro-drug into the active drug. For example, prontosil red is reduced and thus converted to sulphanilamide in a reaction like that shown in figure 4 for the reduction of an azo compound. This allows some compounds to pass safely through the harsh environment of the stomach without reacting after which they can be activated. This may also result in some seemingly safe compounds being converted to toxic compounds.

1. McKee, T., McKee J.R. (2009). Biochemistry the molecular basis of life. (4th ed.). New York (NY): Oxford University Press.
2. Rang, H.P., Dale, M.M., Ritter, J.M., Flower, R.J. (2007) Rang and Dale’s Pharmacology. (6th ed.). China: Elsevier.
3. . Retrieved January 24, 2012.
4. Gibson, G.G., Skett, P. (2001) Introduction to drug metabolism. (3rd ed.). Cheltenham (UK): Nelson Thornes Publishers. Retrieved January 25, 2012.
5. Retrieved January 25, 2012.