Oxidation

Oxidation is a chemical transformation in which a drug molecule loses electrons — typically by having oxygen atoms added to it, or hydrogen atoms stripped away. It is the dominant reaction in Phase I metabolism, the first stage the liver uses to process a foreign compound.

Phase I metabolism primes a molecule for elimination: oxidation makes a drug more polar and water-soluble so the kidneys or bile can eventually clear it. The reaction does not simply inactivate a drug; the metabolites it produces can be pharmacologically active in their own right, or in some cases more harmful than the original compound.

How it works · its role

The enzymes responsible for most oxidative metabolism are the cytochrome P450 (CYP) family — haem-containing proteins that use molecular oxygen and the cofactor NADPH to donate an oxygen atom to the drug molecule. Different CYP isoforms handle different drugs: CYP3A4 is the most abundant and handles the largest share of clinically used drugs; CYP2D6 and CYP2C19 handle many others.

The specific reaction that occurs depends on the drug's molecular structure. Common oxidative reactions include hydroxylation (adding an –OH group), N-dealkylation (removing a methyl or ethyl group attached to nitrogen), O-dealkylation, epoxidation, and sulfoxidation.

Genetic variation shapes how quickly this happens. People carrying slower-acting forms of CYP2D6 metabolise certain drugs more slowly than average, resulting in higher plasma concentrations from a standard dose. Those with ultra-rapid-metaboliser variants clear drugs so fast the therapeutic window may be missed — or, in the case of prodrugs, the active metabolite may accumulate faster than expected.

Relevance to substances & effects

Oxidative metabolism is relevant to a wide range of substance classes. Prodrugs — compounds that are pharmacologically inert until metabolised — depend on oxidation to become active. Codeine is converted to morphine by CYP2D6; people who lack functional CYP2D6 experience little effect from it, while ultra-rapid metabolisers can reach morphine levels that carry overdose risk from a dose considered standard.

Benzodiazepines illustrate a different pattern. Diazepam is oxidised to active metabolites — including nordiazepam and oxazepam — that carry sedative effects of their own and substantially extend the drug's duration beyond what the parent compound alone would produce.

Alcohol follows a related but separate oxidative path: alcohol dehydrogenase converts it first to acetaldehyde, a toxic intermediate, before a second step produces acetate. Substances that block the second enzyme allow acetaldehyde to accumulate, causing flushing, nausea, and rapid heartbeat — the mechanism behind disulfiram and the similar flush reaction seen in people with certain genetic variants.

Because CYP enzymes handle many drugs simultaneously, competition for the same enzyme is one of the primary mechanisms of drug–drug interactions. One substance can inhibit or induce a CYP isoform, raising or lowering plasma levels of anything else metabolised by the same route. The interaction severity ratings across this encyclopedia reflect, in part, whether two compounds share — and compete for — the same oxidative pathway.