MDG5204 Chap.3 Drug Metabolism and Cytochrome P450 Interactions
Drug Metabolism and Cytochrome P450 Interactions
Why drugs are metabolised
The properties that let a drug cross membranes, lipid solubility above all, are the properties that stop the kidney removing it. Metabolism, which the course also calls biotransformation, resolves this by chemically altering the drug, mainly in the liver but also in the intestine, lungs, kidneys and plasma, so that a nonpolar molecule becomes polar enough to leave in urine or bile.
The lecture makes the consequence explicit: without metabolism, lipid-soluble drugs would accumulate and become toxic.
Two phases with different jobs
Phase I reactions are oxidation, reduction and hydrolysis, carried out mainly by cytochrome P450 enzymes in the smooth endoplasmic reticulum. They introduce or expose a functional group such as a hydroxyl, amino or carboxyl group.
Phase II reactions attach an endogenous molecule, such as glucuronic acid, sulfate, glutathione, an acetyl or methyl group or glycine, either to that Phase I product or directly to the parent drug, making it more polar again.
Most metabolites are less active, but some are active or more potent, and a prodrug depends on metabolism to become active at all.
Cytochrome P450 and drug interactions
The name of each enzyme records its family, subfamily and isoenzyme, and CYP3A4 alone handles about half of all drugs. A drug may be a substrate, an inducer or an inhibitor of a particular isoform.
Inducers such as rifampin, phenytoin, carbamazepine and St John's wort increase enzyme expression, speed the metabolism of other drugs and can cause treatment failure; inhibitors such as erythromycin, ketoconazole, ritonavir and grapefruit juice slow it and can cause toxicity.
The lecture's paired cases, rifampin with an oral contraceptive and grapefruit juice with a statin, show the two directions.
Genes, conjugation and special populations
Genetic variation divides patients into poor, extensive and ultrarapid metabolisers, and the consequence depends on whether the parent drug or its metabolite does the work: a poor metaboliser accumulates warfarin but fails to activate clopidogrel or to turn codeine into morphine.
Phase II has its own failures, taught as cases on bilirubin glucuronidation, paracetamol overdose and slow acetylation of isoniazid. Liver disease, the immature enzymes of neonates and the reduced hepatic blood flow of the elderly all lower metabolic capacity.
What this chapter covers
- 01
Biotransformation from nonpolar to polar and why it is needed for excretion
- 02
Phase I oxidation, reduction and hydrolysis against Phase II conjugation
- 03
Cytochrome P450 nomenclature and the dominance of CYP3A4
- 04
Enzyme inducers and inhibitors and the direction of each interaction
- 05
Poor, extensive and ultrarapid metabolisers and prodrug activation
- 06
Glucuronidation, glutathione and acetylation failures and who metabolises less
Worked example · free
Predicting an interaction from a new prescription
- 2Classify each added drug as inducer or inhibitor.
- 2Predict the level and effect with ketoconazole.
- 2Predict the level and effect with carbamazepine.
Key terms
- Biotransformation
- Enzymatic chemical alteration of a drug in the body, mainly turning nonpolar molecules into polar ones.
- Phase I Reaction
- Oxidation, reduction or hydrolysis that introduces or exposes a functional group.
- Phase II Reaction
- Conjugation of an endogenous group to a drug or its metabolite, increasing polarity.
- Cytochrome P450
- A family of haem-containing monooxygenases in the liver and intestine that carry out most Phase I reactions.
- Enzyme Inducer
- A drug or substance that increases expression of a metabolising enzyme and speeds the metabolism of its substrates.
- Enzyme Inhibitor
- A drug or substance that blocks a metabolising enzyme and slows the metabolism of its substrates.
- Prodrug
- An inactive compound that must be metabolised to produce the active drug.
Drug Metabolism and Cytochrome P450 Interactions FAQ
Why does grapefruit juice matter for someone taking a statin?
Grapefruit juice inhibits CYP3A4, the enzyme that metabolises several statins. With the enzyme blocked, the statin is cleared more slowly and its plasma level rises, increasing the risk of dose-related adverse effects. The juice changes the handling of the drug rather than having an effect of its own.
Why can the same codeine dose relieve pain in one person and not another?
Codeine relieves pain mainly after CYP2D6 converts it to morphine. People with little CYP2D6 activity form little morphine and get poor relief, while ultrarapid metabolisers form more and faster. The difference lies in the gene for the enzyme, not in the dose taken.
What makes paracetamol overdose damage the liver?
At normal doses paracetamol is cleared by glucuronidation and sulfation, and the small amount of reactive intermediate is neutralised by glutathione. In overdose glutathione is used up, the reactive metabolite NAPQI accumulates and binds liver cells, causing necrosis. N-acetylcysteine is given to restore that capacity.
Are newborns and older adults at the same risk from slow metabolism?
Both metabolise less, for different reasons. Newborns have immature CYP and UGT enzymes, which is also why neonatal jaundice occurs, while older adults have reduced hepatic blood flow and lower enzyme activity. Both groups may need lower doses of drugs that depend on hepatic metabolism.
Exam move
Learn the inducer and inhibitor lists as two columns you can write from memory, then practise every interaction question by writing the four-step chain from enzyme to effect. For polymorphism questions, decide first whether the parent or the metabolite is active.
Working through Drug Metabolism and Cytochrome P450 Interactions in MDG5204? Sia is AskSia’s AI Pharmacology tutor — ask any MDG5204 Drug Metabolism and Cytochrome P450 Interactions question and get a clear, step-by-step explanation grounded in how MDG5204 is taught and assessed. Read this chapter free, then take your hardest questions to Sia.
