Drug-Metabolizing Enzymes and Transporters
Drug-metabolizing enzymes and transporters are the protein systems that determine how the body processes medicines: enzymes chemically modify drugs so they can be eliminated, while transporters move drugs and their metabolites across cell membranes. Because the genes encoding these proteins are highly variable between individuals, they are a central concern of pharmacogenomics and a major source of differences in drug response.
Definition
Drug-metabolizing enzymes and transporters are, respectively, the enzymes that catalyse the chemical conversion (biotransformation) of drugs and other xenobiotics into more readily excreted forms, and the membrane proteins that carry drugs into and out of cells, together determining the absorption, distribution, metabolism, and elimination of medicines.
Scope
This area orients the reader to the enzymes that carry out drug biotransformation (notably the cytochrome P450 oxidative enzymes and the conjugating enzymes of phase II metabolism) and to the membrane transporters that govern drug uptake and efflux. It frames how genetic variation, enzyme induction, and enzyme inhibition combine to shape drug disposition. It is a reference overview of mechanisms, not a guide to prescribing.
Sub-topics
Core questions
- Which enzymes and transporters handle a given drug, and how do their genetic variants alter its disposition?
- How do phase I and phase II reactions and membrane transport combine to determine drug clearance?
- How do enzyme induction and inhibition produce clinically relevant drug-drug interactions?
Key concepts
- Biotransformation (phase I and phase II metabolism)
- Cytochrome P450 enzyme system
- Drug uptake and efflux transporters
- Genetic polymorphism and metabolizer phenotype
- Enzyme induction and inhibition
- First-pass metabolism and clearance
- Absorption, distribution, metabolism, and elimination (ADME)
Mechanisms
Drug disposition is shaped by the coordinated action of enzymes and transporters. Phase I reactions, dominated by the cytochrome P450 enzymes, introduce or expose functional groups through oxidation, reduction, or hydrolysis; phase II reactions then conjugate the drug or its metabolite with endogenous molecules to increase water solubility and promote excretion (Wilkinson, 2005). In parallel, membrane transporters control how much drug enters cells and tissues and how rapidly it and its metabolites are pumped out, influencing absorption, tissue exposure, and elimination (International Transporter Consortium, 2010). Inherited variation in the genes encoding these proteins changes their amount or activity, so that individuals differ predictably in how they metabolise and transport the same drug (Evans & Relling, 1999; Evans & McLeod, 2003).
Clinical relevance
Understanding these enzyme and transporter systems explains much of the person-to-person variability in drug response and in susceptibility to drug-drug interactions, and provides the mechanistic basis for pharmacogenomic testing. This entry describes how the systems work as a reference for interpreting that variability; it does not provide dosing rules or individualized treatment recommendations.
Epidemiology
Variant alleles affecting drug metabolism and transport are common worldwide, and their frequencies differ markedly across ancestral populations, which is one reason drug response varies between groups. The pharmacogenomic literature documents that a large fraction of widely used medicines is handled by a small number of highly polymorphic enzymes and transporters (Evans & McLeod, 2003).
History
The recognition that inherited differences shape drug response grew out of mid-twentieth-century pharmacogenetics, and accelerated as the genes encoding individual enzymes and transporters were cloned and characterised. The landmark reviews by Evans and Relling (1999) and Evans and McLeod (2003) reframed this body of work as pharmacogenomics, while Wilkinson (2005) synthesised the metabolic basis of interindividual variability, and the International Transporter Consortium (2010) consolidated the parallel importance of membrane transporters.
Key figures
- William Evans
- Mary Relling
- Grant Wilkinson
- Howard McLeod
Related topics
Seminal works
- evans-relling-1999
- evans-mcleod-2003
- wilkinson-2005
- itc-2010
Frequently asked questions
- What is the difference between drug-metabolizing enzymes and drug transporters?
- Enzymes chemically change a drug so it can be broken down and eliminated, whereas transporters physically move the drug and its metabolites across cell membranes into and out of cells; both jointly determine how the body handles a medicine.
- Why do these systems matter for differences in drug response?
- The genes encoding these enzymes and transporters are highly variable between people, so individuals can metabolise or transport the same drug at very different rates, which contributes to differences in effect and in the risk of drug-drug interactions.