Phase I metabolism

An enzymatic reaction in which a “functionalisation” step is carried out on a drug (or possibly on a metabolite). A functional group is either added to, or is revealed on, the drug structure. This functional group, which is often an oxygen-containing group and is sometimes a nitrogen-containing group, may render the drug more water-soluble and easier to excrete in the urine.

The group may also be the point of attack for a phase II metabolic enzyme, which carries out a conjugation reaction, adding a large, (usually) water-soluble group to the drug or metabolite.

Phase I reactions are often carried out by cytochrome P450 enzymes, which oxidise the parent drug. Other phase I reactions carried out by other enzyme systems include reductions, hydrolysis, hydrations and isomerisations. Phase I metabolism, for the majority of drugs, is the event that results in hepatic clearance of the drug. Note that clearance simply refers to removal of the parent drug, but one or more metabolites, possibly possessing therapeutic activity, may persist in the circulation.