BMS 123 · Common Core (Tronc commun)Section 3.3 · Drug metabolism
Section 12 of 27
Phase II conjugation
Explain conjugation, name the six Phase II reactions with their cofactors, describe the fate of conjugates, and trace paracetamol handling at a normal dose and in an overdose.
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Why this matters
Phase II is usually the step that finally gets a drug out of the body, and it contains the commonest conjugation reaction, glucuronidation. It also explains the paracetamol overdose, one of the most frequent drug poisonings, and why some drugs are reabsorbed from the gut and act for much longer than their blood level suggests. Induction and inhibition in the next section act on these same reactions.
What you need to know first
You need section 3.2, especially the four functional groups –OH, –NH₂, –SH and –COOH and the fact that Phase I introduces or unmasks them. You also need the idea that a polar molecule is not reabsorbed by the kidney tubule, while a lipophilic one is.
Words to know (6)
Conjugation
The attachment of a drug or its metabolite to an endogenous compound such as glucuronic acid, sulfate or glutathione, producing a more water-soluble product. Joining a drug to glucuronic acid is a conjugation reaction.
Glucuronidation
Conjugation with glucuronic acid from the cofactor UDP-glucuronic acid; it is the most common and most important Phase II reaction. Most of a normal paracetamol dose leaves the body as a glucuronide.
Transferase
The class of enzyme that catalyses conjugation by moving a chemical group from a cofactor onto the drug; most Phase II transferases are non-microsomal. Sulfotransferase and acetyl transferase are Phase II transferases.
Glutathione
A protective tripeptide (Gly-Cys-Glu) that captures reactive electrophilic metabolites and turns them into non-toxic conjugates. Glutathione neutralises the small amount of reactive metabolite formed from paracetamol each day.
Sulfation (sulfate conjugation)
Conjugation of a sulfate group from sulfotransferase to phenols, catechols, alcohols and amines; it predominates at low substrate concentration. At a low dose a phenol is mainly sulfated rather than glucuronidated.
Enterohepatic recirculation
The cycle in which a biliary conjugate is cleaved by gut bacteria, the drug is reabsorbed, metabolised again and re-excreted, prolonging its action. Oral contraceptives are the example of enterohepatic cycling given in the notes.
One idea at a timeIdea 1 / 7
In one sentence Phase II joins the drug, or its Phase I product, to an endogenous compound, which makes it far more water-soluble and easier to excrete.
Conjugation attaches a large polar partner
Less water-soluble parent drugs, and the Phase I metabolites that carry –OH, –NH₂, –SH or –COOH groups, are conjugated with endogenous compounds to form more water-soluble and more readily excreted conjugates. Phase II reactions are catalysed by transferase enzymes located in the cytoplasm and the endoplasmic reticulum; except for glucuronidation, these transferases are non-microsomal. The reactions require high-energy intermediates, because attaching a polar partner to a reluctant molecule costs energy. The partner is usually derived from carbohydrate, protein or sulfur metabolism, which is why conjugation is sometimes described as borrowing the body’s own building blocks.
For example
A Phase I product carrying an –OH group can be joined to glucuronic acid, a sugar acid supplied by the body, and the resulting conjugate is highly water-soluble.
Pause and check yourself
Which four functional groups are needed for Phase II conjugation, and where do they come from?
Show the answer
–OH, –NH₂, –SH and –COOH. They are already present on some parent drugs, or they are introduced or unmasked by Phase I reactions.
Read detailed explanations
Enterohepatic recirculation: how the gut gives a drug back
Biliary excretion is not always final. High-molecular-weight conjugates, especially glucuronides, pass from the liver into bile and then into the small intestine. There, bacteria of the gut flora produce β-glucuronidase, an enzyme that cleaves the conjugate bond and releases the original drug. The freed drug is lipid-soluble again, so it is reabsorbed, carried back to the liver by the portal vein, conjugated once more and re-excreted in bile. This loop is called enterohepatic recirculation or cycling. Its practical effect is a second, later peak in the plasma concentration curve and a longer apparent half-life, because the body has to process the same molecule several times before it finally leaves in the faeces or urine. Oral contraceptives are the example cited in the lecture notes. The same mechanism explains why antibiotics that alter the gut flora can sometimes change the blood level of a drug that cycles in this way, and why a drug excreted mainly as a biliary conjugate can act for much longer than its plasma half-life alone would suggest. It also gives a reason to ask, for any drug, not only how it is metabolised but where its metabolites go next.
Paracetamol overdose: saturation, glutathione depletion and delayed injury
Two features make paracetamol overdose predictable. First, the ordinary pathways are saturable. Glucuronidation and sulfation behave like fixed-capacity conveyor belts: at a normal dose they carry about 95% of the drug, but as the dose rises they reach their maximum rate, and every further milligram must find another route. Second, the remaining route depends on a limited protective molecule. Glutathione is a tripeptide built from glycine, cysteine and glutamic acid, and its sulfhydryl group captures electrophilic metabolites. At a normal dose the small amount of reactive metabolite formed is neutralised as fast as it appears. In a large overdose the reactive metabolite is produced faster than glutathione can be replaced; the glutathione pool falls, the unconjugated metabolite binds to liver cell proteins and lipids, and hepatocytes die. The injury is therefore dose-dependent and delayed, because it is the exhaustion of a protective pool rather than the direct action of paracetamol that damages the liver. This reasoning generalises: any drug whose safe handling depends on a saturable pathway plus a finite cofactor or antioxidant reserve can show the same dose-dependent jump from safe to toxic.
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The six conjugation reactions
Phase II attaches a water-soluble endogenous partner to the drug. Glucuronidation is the commonest; sulfation, glutathione, acetylation, glycine conjugation and methylation complete the set.
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01 / 6Glucuronidation
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Glucuronidation
Conjugation with glucuronic acid from the abundant cofactor UDP-glucuronic acid. It accepts –OH, –NH₂ and –COOH groups, which makes it the commonest and most important conjugation reaction in the body.
Schematic table, not to scale. Real conjugates differ in molecular weight, which is what decides whether they leave in urine or in bile.
Key points to remember
✓Phase II conjugates –OH, –NH₂, –SH or –COOH groups with endogenous compounds using transferases and high-energy intermediates.
✓The six reactions are glucuronidation, sulfation, glutathione conjugation, acetylation, glycine conjugation and methylation.
✓Glucuronidation is the commonest and most important; sulfation predominates at low substrate concentration and glucuronidation at high concentration.
✓Low-molecular-weight conjugates go to urine; high-molecular-weight conjugates go to bile and may undergo enterohepatic recirculation.
✓Paracetamol: about 95% glucuronide and sulfate plus 5% glutathione normally; in overdose the main routes saturate, glutathione is depleted and a reactive hepatotoxic metabolite forms.
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Worked example
Tracing paracetamol through Phase II at two doses. A patient takes an ordinary therapeutic amount of paracetamol; another takes a very large amount. Both doses are conjugated in the liver. Explain the route each dose takes and why only the second patient develops liver injury.
Ordinary dose, main route: about 95% is conjugated with glucuronic acid and with sulfate. UDP-glucuronic acid is abundant, and sulfotransferase works efficiently while the substrate concentration is low.
Ordinary dose, safety route: the remaining roughly 5% is handled through glutathione, which neutralises the small amount of reactive electrophilic metabolite produced.
Large dose, first consequence: glucuronidation and sulfation reach their maximum rate. They behave like a fixed number of workbenches, so the excess drug cannot be handled by those routes.
Large dose, second consequence: the excess is diverted towards the glutathione route, and glutathione is consumed faster than the liver can replace it.
Once glutathione is depleted, the reactive metabolite binds liver cell proteins and lipids, causing hepatocyte death. The injury is dose-dependent and delayed, because it follows the emptying of a protective reserve.
The same two conjugation reactions run at every dose; what changes is their capacity. A safe drug becomes a poison when a protective pathway is overwhelmed, not because the drug changes its nature.
Common misconception
A common beginner model is that only Phase I can produce toxicity, because Phase II conjugates are described as inactive and water-soluble. In paracetamol overdose the danger comes precisely from the failure of a Phase II protective reaction: the conjugates themselves are harmless, but once the main routes saturate, the reactive metabolite is left unneutralised.
Check your reasoning
A drug is excreted in bile as a glucuronide and then reappears in the blood several hours later. Explain the mechanism and say what it means for the dosing interval.
Reveal an answer
Gut bacteria produce glucuronidase, which cleaves the conjugate and releases the lipid-soluble drug; it is reabsorbed, metabolised again and re-excreted. This enterohepatic recirculation creates a second peak and prolongs the apparent half-life, so the drug can act longer than a single passage through the liver would suggest.
Where this comes from
BMS 123 General Pharmacology II lecture notes · Lecture 3: Phase II pathways — conjugation reactions, fate of conjugates and paracetamol toxicity
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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.