Drug Metabolism and Biotransformation

Drug metabolism, or biotransformation, is the enzymatic conversion of a drug into other chemical species — usually more water-soluble metabolites that are more readily excreted. It is the body's principal means of terminating the action of many drugs, and it is also the source of much pharmacokinetic variability and of many drug-drug interactions.

Definition

Drug metabolism (biotransformation) is the enzyme-catalysed chemical modification of a drug, typically converting it to more polar metabolites; phase I reactions introduce or expose functional groups (chiefly by oxidation), and phase II reactions conjugate the drug or its phase I product with an endogenous molecule.

Scope

The entry covers the phase I and phase II reactions of biotransformation, the cytochrome P450 enzyme system, the formation of active and reactive metabolites, the regulation of metabolising enzymes by xenobiotic receptors, and the basis of metabolic drug interactions. It is a conceptual reference and gives no dosing guidance.

Core questions

• Which enzymes carry out biotransformation, and how do phase I and phase II reactions differ?
• How does metabolism convert drugs into more readily excreted, and sometimes more or less active, species?
• How do cytochrome P450 enzymes underlie many drug-drug interactions?
• What regulates the expression of drug-metabolising enzymes?

Key concepts

• Phase I (oxidation, reduction, hydrolysis)
• Phase II (conjugation: glucuronidation, sulfation, acetylation)
• Cytochrome P450 (CYP) enzyme families
• Active and reactive metabolites
• Prodrug activation
• Enzyme induction and inhibition
• First-pass (presystemic) metabolism
• Pharmacogenetic variation in metabolism

Key theories

Phase I / phase II framework of biotransformation

Organises metabolism into functionalisation reactions (phase I, predominantly cytochrome P450-mediated oxidation) that introduce or unmask reactive groups, and conjugation reactions (phase II) that attach polar endogenous moieties to yield highly water-soluble, readily excreted products.

Xenobiotic-receptor regulation of metabolising enzymes

Ligand-activated nuclear receptors (such as PXR and CAR) sense drugs and other xenobiotics and induce the enzymes and transporters that dispose of them, providing a molecular basis for enzyme induction and adaptive metabolic responses.

Mechanisms

Biotransformation generally proceeds in two coordinated phases. Phase I reactions — most importantly oxidations catalysed by the cytochrome P450 (CYP) superfamily — introduce or expose polar functional groups; phase II reactions then conjugate the drug or its phase I metabolite with glucuronic acid, sulfate, glutathione, or other endogenous molecules to produce highly water-soluble products suited to excretion. Metabolism usually inactivates a drug, but it can also generate active metabolites or activate a prodrug, and occasionally yields chemically reactive metabolites implicated in toxicity. Because individual CYP enzymes handle many substrates, one drug can inhibit or induce the metabolism of another, producing drug-drug interactions; xenobiotic-sensing nuclear receptors such as PXR and CAR mediate induction by up-regulating the relevant enzymes.

Clinical relevance

Metabolism is a major determinant of how long and how strongly a drug acts and a leading source of drug-drug interactions and inter-individual variability, which is central to interpreting drug exposure. This entry is a mechanistic reference and does not provide individualised treatment or dosing advice.

Evidence & guidelines

The cytochrome P450 framework and the use of probe substrates and inhibitors underpin regulatory guidance on assessing metabolic drug-drug interactions during drug development, and the phase I / phase II scheme is codified across pharmacology and clinical-pharmacokinetics texts.

History

Systematic study of biotransformation grew through the twentieth century as oxidative, reductive, and conjugative reactions were catalogued and organised into the phase I and phase II scheme. The discovery and characterisation of cytochrome P450 as a versatile oxidising enzyme system transformed the field, explaining both the breadth of drug oxidation and the basis of many interactions. Later identification of xenobiotic-sensing nuclear receptors clarified how exposure to drugs induces the enzymes that metabolise them.

Key figures

• F. Peter Guengerich
• Bert N. La Du
• Allan H. Conney
• Shiew-Mei Huang

Seminal works

• guengerich-2007
• mackowiak-2018

Frequently asked questions

What is the difference between phase I and phase II metabolism?

Phase I reactions (mainly cytochrome P450 oxidations) introduce or expose reactive functional groups, while phase II reactions conjugate the drug or its phase I product with a polar endogenous molecule to make it water-soluble and readily excreted.

Does metabolism always inactivate a drug?

No. Metabolism usually inactivates a drug, but it can also produce pharmacologically active metabolites, activate an inactive prodrug, or occasionally generate reactive metabolites associated with toxicity.