phase I metabolism

Phase I metabolism is the body's way of putting a chemical 'handle' onto a drug. Many drugs are greasy molecules with no convenient spot for the body to grab and eliminate them, so the first step is to bolt on a small reactive group — most often by adding oxygen. Once that handle exists, later steps can attach something bulky to flush the drug out.

Mechanistically, phase I reactions are functionalization reactions: oxidation, reduction, and hydrolysis. Oxidation, dominated by the cytochrome P450 enzymes, is by far the most common and includes hydroxylation, N- and O-dealkylation, and epoxidation. These reactions either unmask or introduce polar groups such as hydroxyl, amino, or carboxyl, making the molecule slightly more water-soluble and giving phase II enzymes a site to act on.

Phase I does not always lead to harmless products. Adding a reactive group can deactivate a drug, but it can also convert an inactive prodrug into its active form, or generate a chemically reactive metabolite capable of binding cellular proteins and causing toxicity. Because of this, medicinal chemists study not just how fast a compound is metabolized but exactly where and into what.