Metabolism

Metabolism is the set of chemical transformations the body performs on a drug after it enters the bloodstream — converting it, step by step, into compounds that can be excreted. Most of this work happens in the liver, though the gut wall, kidneys, and lungs also contribute.

The resulting compounds are called metabolites. They may be pharmacologically inactive, retain some activity, or in certain cases be more potent than the substance that produced them. This last possibility is why metabolism is not simply a process of inactivation — it is a transformation, and the transformed product has its own effects and timeline.

How it works · its role

Drug metabolism proceeds in two broad phases. Phase I reactions — primarily oxidation, reduction, and hydrolysis — chemically alter the original molecule to make it more water-soluble. These are carried out largely by the cytochrome P450 (CYP) enzyme family, a group of proteins concentrated in liver cells. Phase II reactions then attach larger molecules (glucuronic acid, sulfate, or glycine) to the product, rendering it soluble enough to be filtered by the kidneys.

The CYP enzymes are not uniform. Different isoforms — CYP3A4, CYP2D6, CYP1A2, among others — handle different substrates, and their activity varies considerably between individuals due to genetics, age, and the presence of other drugs. A person carrying certain genetic variants may metabolize a substance slowly, letting it accumulate, or very rapidly, clearing it before much effect is felt.

Some substances are prodrugs: biologically inactive until metabolism produces their active form. Codeine generates most of its opioid effect only after CYP2D6 converts a portion of it to morphine — a step that poor metabolizers of that enzyme perform only minimally.

Relevance to substances & effects

Metabolism shapes nearly every aspect of a drug's profile — onset, duration, intensity, and interaction risk. When a drug is taken orally, it passes through the gut wall and liver before reaching the general circulation. This first-pass effect can substantially reduce the amount reaching the bloodstream, which is why the same compound often requires much lower doses by routes that bypass the liver, such as inhalation or sublingual absorption.

Active metabolites extend or transform a drug's effects in ways the dose alone does not predict. THC, for example, is converted in the liver to 11-hydroxy-THC, a compound thought to cross the blood–brain barrier efficiently and contribute to the stronger, longer-lasting effects commonly reported with oral cannabis compared with inhaled.

Many drug interactions operate at the metabolic level. One substance can inhibit a CYP enzyme, causing a co-administered drug to accumulate beyond expected levels. Others induce the same enzyme, accelerating the clearance of substances processed through it. MAOIs illustrate both the mechanism and the stakes: by blocking monoamine oxidase — an enzyme that degrades certain amines — they can push co-administered serotonergic or stimulant compounds to dangerous levels. Specific interaction severities for individual pairings are documented in the encyclopedia's interaction layer, where the supporting evidence lives.