BMS 123 · Common Core (Tronc commun)Section 3.1 · Drug metabolism
Section 10 of 27
Why the body metabolises drugs
Explain what drug metabolism is, why the body must change drugs before it can excrete them, and where the metabolising enzymes are found.
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Why this matters
Metabolism is the first half of elimination, so it decides how long a drug acts and how strong its effect becomes. It also explains why only part of a swallowed dose reaches the blood, why a tablet can fail in one patient and work in another, and why some drugs damage the liver only after a large overdose. Every other section of this unit builds on the ideas taught here.
What you need to know first
You need the four ADME steps from Unit 1 — absorption, distribution, metabolism and excretion — and the idea from Unit 2 that drugs travel in the blood and pass into tissues. Nothing else is assumed: every new word is defined in this section.
Words to know (6)
Biotransformation (drug metabolism)
The chemical change of a drug inside the body, which usually makes it more water-soluble and easier to eliminate. The liver turning a fat-soluble painkiller into a water-soluble product is biotransformation.
Metabolite
The substance produced when an enzyme changes a drug; it may be inactive, still active, or more toxic than the parent drug. Ethanol is oxidised first to acetaldehyde, a metabolite that is itself toxic.
Microsomal enzymes
Metabolising enzymes fixed in the smooth endoplasmic reticulum of liver, kidney and gut cells; they are less selective for their substrates. The CYP450 oxidases that handle most drugs are microsomal enzymes.
Non-microsomal enzymes
Metabolising enzymes found free in the cytoplasm and in mitochondria of different organs; they act on a narrower range of substrates. Esterases and reductases that work in the cytoplasm are non-microsomal enzymes.
Cytochrome P450 (CYP450)
A superfamily of microsomal monooxygenase enzymes that oxidise most drugs; it is the main drug-metabolising system in humans. Two drugs can compete for the same CYP450 enzyme and change each other’s blood level.
Prodrug
An inactive substance that must be changed by the body before it can produce its effect. A prodrug has no action of its own; only its metabolite acts.
One idea at a timeIdea 1 / 7
In one sentence Elimination — metabolism plus excretion — is what stops a drug acting and keeps it from piling up in the body.
Elimination ends the effect and prevents accumulation
Once a drug enters the body, the process of elimination begins. Elimination is essential to terminate the drug’s effects — both the effects we want and the ones we do not want — and to prevent excessive accumulation and toxicity. Elimination has two halves: metabolism, also called biotransformation, changes the drug chemically, and excretion removes the drug and its products from the body. These are separate processes with different organs. Metabolism prepares the molecule; excretion finally expels it. A drug that were never eliminated would accumulate a little more with every dose until the level became dangerous.
For example
A painkiller wears off after a few hours because the liver has changed it and the kidneys have removed the products; without those two steps, every repeat dose would simply add to the last one.
Pause and check yourself
Which two processes make up drug elimination, and why is elimination necessary?
Show the answer
Metabolism and excretion. Elimination ends the drug’s wanted and unwanted effects and prevents the drug from accumulating to a toxic amount.
Read detailed explanations
Why the liver is the main site: anatomy, enzymes and first pass
The liver earns its place in three ways. First, anatomy: almost every swallowed drug is absorbed into the hepatic portal vein, so the liver meets the drug before the rest of the body does, and in a healthy adult it receives roughly a quarter of the resting cardiac output. Second, chemistry: hepatocytes are packed with smooth endoplasmic reticulum, the membrane system that carries the microsomal enzymes, so the concentration of metabolising enzymes per gram of tissue is higher there than anywhere else. Third, consequence: this arrangement creates the first-pass effect. A swallowed dose passes through the gut wall and then the liver, and part of it is changed before it ever reaches the general circulation, which is why the same drug given by mouth and by vein can produce very different blood levels. A patient with cirrhosis has fewer working hepatocytes, so the same dose is metabolised more slowly and can accumulate. A patient in heart failure has poorer liver blood flow, which slows metabolism in a different way. The liver is therefore not a passive filter but a chemical workshop whose output depends on blood supply, enzyme content and the drug itself.
Reading the CYP450 code: isoforms, saturation and variability
CYP450 names are written as a family number, a subfamily letter and an individual number: CYP3A4 means family 3, subfamily A, enzyme 4. Enzymes in one family share more than 40% of their amino-acid sequence; within a subfamily they are more similar still, yet they overlap in the drugs they accept. That overlap explains the central paradox of the system: it is broad enough to handle thousands of foreign chemicals, and imprecise enough that two drugs can compete for the same active site. Three properties follow. Low specificity means one enzyme handles many substrates, so a single inhibitor may raise the level of several drugs at once. Saturation means the enzyme behaves like a fixed number of workbenches: once every bench is busy, adding more drug does not speed the reaction and the drug accumulates — the mechanism behind paracetamol overdose in section 3.3. Variability and inducibility mean that two people given the same dose can have very different blood levels, and that a second drug, or a habit such as smoking, can reset the workshop. About 50 isoforms are active in humans and the CYP1, CYP2 and CYP3 families handle most medicines, which is why almost every important drug–drug interaction involves this small group.
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Where drugs are metabolised
The liver is the main site of metabolism, but the gut, lungs, kidneys and plasma also carry metabolising enzymes, and microsomal and non-microsomal enzymes work in different compartments.
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01 / 6Liver (main site)
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Liver (main site)
The liver contains the highest amounts of drug-metabolising enzymes and receives blood straight from the intestine through the portal vein. It is therefore the main site of biotransformation, and also the source of the first-pass effect.
Schematic body outline, not to scale. The relative size of each organ does not represent its share of metabolism; the liver handles by far the largest part.
Key points to remember
✓Elimination = metabolism + excretion; it ends drug effects and prevents accumulation.
✓Most drugs are lipophilic, which helps absorption and distribution but slows renal excretion.
✓Biotransformation makes drugs more polar, hydrophilic and ionisable so that they can be excreted.
✓The main site is the liver; the gut lumen and wall, lungs, kidneys and plasma also metabolise drugs.
✓Microsomal enzymes (smooth endoplasmic reticulum) are less selective; non-microsomal enzymes (cytoplasm, mitochondria) are more selective.
✓CYP450 is a superfamily of microsomal monooxygenases: over 1000 isoforms, about 50 active in humans, mainly CYP1, CYP2 and CYP3.
Go deeper
Worked example
Following one swallowed tablet from mouth to urine. A patient swallows a 500 mg tablet of a fat-soluble drug. You are asked to trace what happens to the dose, using only the vocabulary of metabolism, and to explain why the blood level never reaches 500 mg.
The tablet disintegrates and the drug dissolves in the gut fluid, then crosses the intestinal wall into the portal blood — the absorption step.
In the intestinal wall and then in the liver, microsomal CYP450 enzymes oxidise part of the dose. A polar group such as –OH is added, so the metabolite is more water-soluble than the parent drug.
This loss before the drug reaches the general circulation is the first-pass effect. It is why the amount that finally arrives is smaller than the amount swallowed.
The surviving parent drug distributes to tissues, produces its effect, then returns to the liver, where further oxidation and then conjugation turn it into a highly polar product.
Because the product is now hydrophilic and ionised in the urine, it is not reabsorbed by the kidney tubule and leaves in the urine. The unchanged parent drug, being fat-soluble, would largely have been reabsorbed.
Metabolism does not remove the drug; it changes it into a form that excretion can remove. The same two steps also decide how much of the swallowed dose ever reaches the tissues, which is why the oral and intravenous routes can differ so much.
Common misconception
Beginners often say that the liver “destroys” a drug, or treat metabolism and excretion as the same thing. Metabolism changes the molecule; it does not remove it from the body, and it can also make a drug more active. Excretion is the separate step that removes the drug and its products.
Check your reasoning
A drug is fat-soluble and passes easily into the brain. Explain why the same property that makes it act quickly also makes its effect last longer than expected.
Reveal an answer
Lipophilicity lets the drug cross membranes quickly in both directions, so it enters the brain fast and also leaves the watery filtrate of the kidney by diffusing back into the blood. Until metabolism adds polar groups, the kidney cannot excrete it efficiently, so the drug remains in the body and its effect is prolonged.
Where this comes from
BMS 123 General Pharmacology II lecture notes · Lecture 3: Drug metabolism — Introduction, sites of metabolism and metabolising enzymes
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About this course and its sources
Bilingual lessons organised from the supplied BMS 123 General Pharmacology II lecture notes (Principles of Pharmacokinetics and Principles of Pharmacodynamics). Diagrams are original educational schematics; pharmacology, nursing and French-language review are pending.