Metabolic pathway

A metabolic pathway is the ordered sequence of chemical transformations the body uses to process a substance — breaking it down, modifying it, and preparing it for elimination. Each step is catalysed by a specific enzyme, most of them concentrated in the liver, though the gut wall, lungs, and kidneys also contribute.

The process serves a practical purpose: most psychoactive substances are fat-soluble and cannot be excreted efficiently by the kidneys. The pathway converts them into more water-soluble metabolites that can leave the body in urine or bile. What is eliminated is rarely chemically identical to what was taken.

How it works · its role

Metabolism generally proceeds in two phases. Phase I reactions — carried out mainly by cytochrome P450 (CYP) enzymes — add or expose reactive chemical groups through oxidation, reduction, or hydrolysis. Phase II reactions then conjugate the product to a larger molecule, such as glucuronic acid, making it polar enough to excrete.

A small number of CYP isoforms — principally CYP3A4, CYP2D6, and CYP1A2 — handle the majority of psychoactive substances. Because each enzyme has limited capacity, two substances that share the same isoform compete for it. One can slow the other's clearance, raising its blood concentration beyond the expected range.

Pathways do not always produce inert end-products. Some substances are converted into pharmacologically active metabolites — codeine, for instance, requires CYP2D6 to transform it into morphine before it can act. Substances that depend on metabolism for their effect are called prodrugs.

Relevance to substances & effects

Metabolic pathways underlie many of the drug interactions flagged across these pages. When one substance inhibits a CYP enzyme, other drugs sharing that pathway accumulate — sometimes to dangerous concentrations. MAOIs illustrate this at a different level: they disable monoamine oxidase, the enzyme responsible for breaking down tyramine and several neurotransmitters, which explains their broad and serious interaction profile.

Cannabis offers a clear example of pathway complexity. THC is oxidised to 11-OH-THC, an active metabolite that crosses the blood-brain barrier readily and contributes to the slower, more intense onset typically seen with oral ingestion compared with inhalation. A further conversion produces 11-COOH-THC, an inactive compound that persists for days and accounts for prolonged detection windows.

Genetic variation adds a further layer. The CYP2D6 gene exists in forms that produce little or no functional enzyme in a subset of people (poor metabolisers) and greatly amplified activity in others (ultra-rapid metabolisers). The same dose of a CYP2D6-dependent substance can be nearly inactive in one person and disproportionately potent in another — a reminder that pathway biology, not dose alone, shapes individual response.