PHC5005 Chap.3 Drug Metabolism, CYP Enzymes and Interactions
Drug Metabolism, CYP Enzymes and Interactions
Elimination has two halves
The course defines elimination as the irreversible loss of a drug from the body and splits it into metabolism and excretion. Clearance is the composite measure of both: the volume of plasma cleared of drug per unit time.
Two relationships carry most of the arithmetic, clearance as the rate of elimination divided by plasma concentration, and clearance as 0.693 times the volume of distribution divided by the half-life.
They connect this chapter to the dosing chapters that follow.
Why the body rebuilds drugs
Biotransformation is the enzymatic alteration of a drug, mostly in the liver, that converts lipid-soluble compounds into polar ones. Polarity is what lets the kidney and bile carry a compound away; without metabolism a lipid-soluble drug would keep diffusing back and accumulate.
The usual result is inactivation, but metabolism can also turn an inactive prodrug into an active drug or an active drug into an active metabolite, which is why its failure can cause either toxicity or loss of effect.
Phase I and Phase II
Phase I reactions, oxidation, reduction and hydrolysis, introduce or expose a functional group such as a hydroxyl, amine or carboxyl.
They happen in the smooth endoplasmic reticulum and are dominated by the cytochrome P450 monooxygenases. Phase II reactions attach an endogenous group, glucuronic acid, sulfate, glutathione, an acetyl or methyl group, or glycine, and take place mainly in the cytosol through transferases such as UGT, GST and NAT.
The lecture's analogy is that Phase I is a preparation crew fitting handles that Phase II enzymes then grab to carry the drug out.
CYP enzymes and interactions
CYP names follow family, subfamily and isoenzyme, and CYP3A4/5 metabolises the largest share of drugs. Any drug may act as a substrate, an inducer or an inhibitor.
Inducers such as rifampin, phenytoin, carbamazepine, St John's wort and smoking accelerate metabolism of other drugs and reduce their response. Inhibitors such as erythromycin, cimetidine, ketoconazole, ritonavir and grapefruit juice slow it and raise toxicity.
The lecture's cases are an unplanned pregnancy after rifampin and rising statin levels with grapefruit juice.
Variation between people
Genetic polymorphism divides patients into extensive, ultrarapid and poor metabolisers.
Its consequences depend on whether the drug is active or a prodrug: poor CYP2C9 activity raises warfarin bleeding risk, while poor CYP2C19 or CYP2D6 activity leaves clopidogrel or codeine unactivated. Phase II has its own examples in UGT1A1 and bilirubin, glutathione and paracetamol overdose, and NAT2 acetylator status with isoniazid.
Liver disease, the neonatal period and old age reduce metabolic capacity, and the course expects dose adjustment and monitoring to follow.
What this chapter covers
- 01
Elimination as metabolism plus excretion, and clearance as their combined measure
- 02
Biotransformation from nonpolar to polar, with inactivation, activation and active metabolites
- 03
Phase I functionalisation against Phase II conjugation
- 04
CYP450 nomenclature and the dominance of CYP3A4
- 05
Enzyme induction and inhibition as drivers of drug-drug interactions
- 06
Metaboliser phenotypes and their consequences for active drugs and prodrugs
- 07
UGT1A1, glutathione and NAT2 cases from Phase II
Worked example · free
Explaining an interaction from its mechanism
- 1Classify rifampin's role in the interaction.
- 3State what that role does to the enzyme and to the contraceptive.
- 2Name the clinical consequence and the lesson for prescribing.
Key terms
- Clearance
- The volume of plasma cleared of a drug per unit time, reflecting metabolism and excretion together.
- Biotransformation
- Enzymatic alteration of a drug in the body, chiefly in the liver, that converts nonpolar compounds into polar ones.
- Phase I Reaction
- Oxidation, reduction or hydrolysis that introduces or unmasks a functional group, largely by CYP enzymes.
- Phase II Reaction
- Conjugation of an endogenous group such as glucuronic acid, sulfate or glutathione to a drug or its metabolite.
- Enzyme Inducer
- A drug or substance that increases metabolising enzyme expression and lowers levels of co-administered substrates.
- Enzyme Inhibitor
- A drug or food that slows metabolism by an enzyme, raising levels and toxicity risk of its substrates.
- Prodrug
- An inactive or weakly active compound that metabolism converts into the active drug, as with clopidogrel and codeine.
- Slow Acetylator
- A person with reduced NAT2 activity who clears drugs such as isoniazid slowly and is prone to their toxicity.
- NAPQI
- The reactive paracetamol intermediate normally neutralised by glutathione and responsible for liver necrosis in overdose.
Drug Metabolism, CYP Enzymes and Interactions FAQ
Is clearance the same thing as excretion?
No. Excretion is one of the two processes that remove a drug; metabolism is the other. Clearance is the composite estimate of all elimination mechanisms, expressed as a volume of plasma cleared per unit time, so a patient with healthy kidneys can still have low clearance if liver metabolism is impaired.
Why does metabolism make drugs more polar?
The kidneys and bile remove polar compounds efficiently, while lipid-soluble molecules diffuse back across membranes and are retained. Converting a nonpolar drug into a polar product is what allows elimination; without it, lipid-soluble drugs would accumulate and cause toxicity.
What does CYP3A4 stand for?
CYP names a cytochrome P450 enzyme, the number 3 is its family, the letter A its subfamily and the final 4 the individual isoenzyme. CYP3A4/5 is the most important isoform in drug metabolism because it handles the largest number of drugs.
Why is grapefruit juice a classic interaction?
It inhibits CYP3A4. Drugs metabolised by that enzyme, statins in the course's example, are cleared more slowly, so their plasma levels rise and the risk of dose-related adverse effects increases even though the prescribed dose has not changed.
How does paracetamol overdose damage the liver?
Normally most paracetamol is glucuronidated or sulfated, and a small amount of the reactive intermediate NAPQI is neutralised by glutathione. In overdose the conjugating routes saturate, glutathione is depleted, NAPQI forms toxic adducts and hepatic necrosis follows. N-acetylcysteine is the treatment.
Why do fast and slow acetylators respond differently to isoniazid?
NAT2 activity is genetically polymorphic. Slow acetylators clear isoniazid slowly and accumulate it, so they develop toxicity such as peripheral neuropathy. Fast acetylators clear it quickly and may show a reduced therapeutic response. Knowing a patient's acetylator type from a genetic test helps set the dose.
Why are older adults often switched to drugs such as lorazepam?
Ageing reduces hepatic blood flow and Phase I oxidation while Phase II conjugation is largely preserved. Drugs that rely on conjugation, such as lorazepam and oxazepam, are therefore handled more predictably than Phase I-dependent drugs such as diazepam.
Exam move
Sort every drug the lecture names into a three-column table, substrate, inducer or inhibitor, and add a fourth column saying whether it is a prodrug. Before any interaction question, place both drugs in the table; the direction of the answer then follows mechanically.
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