MCHM3001 · From Molecules to Therapeutics
ADME & Drug Metabolism
Lectures 16–17 of MCHM3001 cover what the body does to a drug — absorption, distribution, metabolism and excretion — with a focus on the cytochrome-P450 enzymes and the medicinal-chemistry tactics that stabilise a molecule against unwanted metabolism. The examinable core is the CYP450 catalytic cycle and reaction, and predicting and blocking metabolic soft spots. It appears in Test 2 and the final.
What this chapter covers
- 01ADME: absorption (Lipinski balance), distribution (plasma-protein binding, capillary pores), metabolism, excretion
- 02Phase I enzymes: FMO, MAO, esterases/peptidases and the cytochrome P450s (>90% of drug oxidation)
- 03CYP450s: heme monooxygenases named for the 450 nm Soret band; dominant isoform CYP3A4; oxidation R-H + O₂ + 2H⁺ + 2e⁻ → R-OH + H₂O
- 04The CYP catalytic cycle: substrate binding, two electron transfers, O₂ binding, Compound I (Fe(IV)=O porphyrin radical), H-abstraction and rebound
- 05Phase II conjugation converting lipophilic metabolites to polar excretable ones (e.g. paracetamol → paracetamol sulfate)
- 06Metabolic soft spots and stabilising tactics: steric shields, electronic effects, methyl/fluorine blocks, deuterium (deutetrabenazine)
- 07Group shifts to protect a vulnerable group (salbutamol vs noradrenaline)
- 08Destabilising ('soft drug') tactics for ultra-short action (remifentanil, esmolol)
Predicting a metabolic soft spot and blocking it
- +1(a) Identify the enzyme: cytochrome P450 (a heme monooxygenase, most often CYP3A4) carries out aromatic hydroxylation of the electron-rich position.
- +1(a) Write the overall CYP oxidation: R-H + O₂ + 2H⁺ + 2e⁻ → R-OH + H₂O — one oxygen atom is inserted into the C-H bond, the other is reduced to water.
- +1(b) Tactic 1 — fluorine block: replace the labile para C-H with C-F. The C-F bond (~108 kcal/mol) is essentially inert to oxidation and fluorine also lowers the ring's electron density, reducing electrophilic oxidation; this directly protects the soft spot while barely changing the molecule's size.
- +1(b) Tactic 2 — deuterium or steric/electronic shielding: substitute deuterium at the metabolised position (the stronger C-D bond slows CYP H-abstraction, as in deutetrabenazine), or add a steric shield/electron-withdrawing group nearby to hinder enzyme approach or deactivate the ring. Either lengthens half-life by cutting the oxidation rate.
Key terms
- ADME
- Absorption, Distribution, Metabolism, Excretion — what the body does to a drug; it governs exposure and half-life alongside potency.
- Cytochrome P450 (CYP)
- A family of heme monooxygenases (named for the 450 nm Soret band) that carry out most Phase I drug oxidation; CYP3A4 is the dominant isoform. Overall reaction: R-H + O₂ + 2H⁺ + 2e⁻ → R-OH + H₂O.
- CYP catalytic cycle
- The sequence of substrate binding, two one-electron reductions, O₂ binding and formation of the reactive Compound I (Fe(IV)=O porphyrin cation radical) that abstracts a hydrogen and rebounds to hydroxylate the substrate.
- Phase I / Phase II metabolism
- Phase I introduces or exposes a polar group (oxidation by CYP, etc.); Phase II conjugates it (e.g. sulfation, glucuronidation) to make a water-soluble, excretable metabolite.
- Metabolic soft spot
- A site on a molecule especially prone to enzymatic (often CYP) attack; identifying and blocking it (fluorine, deuterium, steric/electronic shields) improves metabolic stability.
- Deuterium switch
- Replacing metabolically labile C-H bonds with C-D; the stronger bond slows CYP-mediated abstraction and can extend half-life (e.g. deutetrabenazine, the first deuterated FDA drug).
ADME & Drug Metabolism FAQ
What reaction do cytochrome P450s catalyse, and why does it matter?
CYP450s are heme monooxygenases that oxidise otherwise unreactive C-H bonds: R-H + O₂ + 2H⁺ + 2e⁻ → R-OH + H₂O, inserting one oxygen atom into the substrate and reducing the other to water via the highly reactive Compound I intermediate. It matters because this Phase I oxidation is how most drugs are cleared, so where a CYP attacks a molecule sets its half-life and can create active or toxic metabolites.
How do you improve a drug's metabolic stability?
You find the metabolic soft spot and protect it. Common tactics are a fluorine block (the inert C-F bond resists oxidation and lowers ring electron density), a deuterium switch (the stronger C-D bond slows CYP hydrogen abstraction), a methyl or steric shield that hinders the enzyme's approach, and electronic changes such as incorporating ring nitrogens to deactivate an aromatic toward oxidation. Each cuts the oxidation rate and lengthens half-life.
What is the difference between Phase I and Phase II metabolism?
Phase I reactions (mostly CYP oxidations, plus FMO, MAO and hydrolysis) add or unmask a polar handle on the molecule. Phase II reactions then conjugate that handle — for example sulfation or glucuronidation — producing a much more water-soluble metabolite that the kidneys can excrete. Paracetamol formation then sulfation is the textbook two-step example, with logP falling at each stage.
Can AI help me with the ADME and metabolism material?
Yes. Sia can walk through the CYP catalytic cycle and the overall oxidation equation, help you predict a likely metabolic soft spot on a structure, and explain stabilising tactics such as fluorine and deuterium blocks. It explains the mechanism and checks your reasoning; it does not do graded assessment for you, and University of Sydney academic-integrity rules apply.
Exam move
Make the CYP450 story your backbone: be able to write the overall oxidation (R-H + O₂ + 2H⁺ + 2e⁻ → R-OH + H₂O), name CYP3A4 as the dominant isoform, and sketch the catalytic cycle through Compound I. Then practise the two-way skill the exam loves — look at a structure, predict where it will be metabolised (electron-rich aromatics, benzylic/allylic C-H, exposed alkyls), and propose a specific block (fluorine, deuterium, steric shield). Keep Phase I versus Phase II straight and hold one worked stabilisation example ready. When the catalytic cycle blurs, ask Sia to redraw it step by step and quiz you on soft-spot prediction.
Working through ADME & Drug Metabolism in MCHM3001? Sia is AskSia’s AI Chemistry tutor — ask any MCHM3001 ADME & Drug Metabolism question and get a clear, step-by-step explanation grounded in how MCHM3001 is taught and assessed. Read this chapter free, then take your hardest questions to Sia.
