Metabolism

Biotransformation is the enzymatic alteration of a drug's chemical structure, primarily to increase its water solubility so the kidneys can excrete it. Without metabolism, many lipid-soluble drugs would be reabsorbed indefinitely in the renal tubules and accumulate to toxic levels. The liver is the dominant metabolic organ because of its enzyme density and its position downstream of the gut in the portal circulation, but the intestinal wall, kidneys, lungs, and plasma also contribute.

Phase I: Functionalization

Phase I reactions introduce or expose a reactive chemical group — a hydroxyl, amine, or carboxyl — through oxidation, reduction, or hydrolysis. Oxidation is the most common and is carried out largely by the cytochrome P450 (CYP450) superfamily, a group of heme-containing enzymes concentrated in hepatocyte smooth endoplasmic reticulum. Different CYP isoforms (such as CYP3A4 or CYP2D6) handle different drug classes, and a single drug may be a substrate for more than one isoform. This subject's sibling topic covers how these isoforms interact with specific drugs; here, the key point is that CYP450 is the workhorse of Phase I functionalization. Phase I products are often more chemically reactive and, in a subset of cases, more pharmacologically active or even toxic than the parent compound.

Phase II: Conjugation

Phase II reactions attach a large, polar molecule — glucuronic acid, sulfate, glycine, or an acetyl or methyl group — to the drug or its Phase I metabolite. Glucuronidation is the most frequent pathway. Conjugation almost always yields an inactive, highly water-soluble product suited for excretion in urine or bile. Phase I and Phase II are not strictly sequential; some drugs undergo conjugation directly, and others skip Phase I altogether.

Prodrugs and Active Metabolites

Most metabolism inactivates a drug, but two important exceptions deserve attention. A prodrug is administered in an inactive or less-active form and requires metabolic conversion to produce its therapeutic effect; this strategy can improve absorption, target a specific tissue, or reduce direct toxicity of the parent compound. An active metabolite is a breakdown product that retains pharmacological activity, meaning the drug's clinical effect can persist, or even intensify, after the original molecule has been transformed. Both concepts complicate dosing: a patient who metabolizes a prodrug poorly may get little benefit, while one who accumulates an active metabolite may experience unexpectedly prolonged effects.

First-Pass Metabolism

Orally administered drugs are absorbed into the portal circulation and travel directly to the liver before reaching systemic circulation. If an enzyme system extensively metabolizes the drug during this initial passage, only a fraction of the original dose reaches systemic circulation intact — this is first-pass metabolism, and it explains why some drugs require much higher oral doses than intravenous doses, or cannot be given orally at all.

Enzyme Induction and Inhibition

Metabolic capacity is not fixed. Enzyme induction occurs when a substance increases the synthesis of metabolic enzymes over days to weeks, accelerating the clearance of drugs handled by that pathway and potentially reducing their effectiveness. Enzyme inhibition occurs when a substance directly blocks enzyme activity, often within hours, slowing clearance and raising blood levels of affected drugs toward toxicity. Both phenomena are central to drug interactions, addressed in depth elsewhere in this curriculum.

Patient Factors

Metabolic capacity varies widely. Liver disease (cirrhosis, hepatitis) reduces enzyme mass and blood flow, prolonging drug action. Age matters at both extremes: neonates have immature enzyme systems, and older adults often have reduced hepatic mass and blood flow. Genetic polymorphisms create "poor," "extensive," or "ultrarapid" metabolizer phenotypes for specific CYP enzymes, meaning identical doses can produce very different blood levels between individuals. Nutritional status also contributes, since malnutrition and certain vitamin deficiencies can impair the cofactors and protein synthesis that enzymatic metabolism depends on.