BMS 123 · Common Core (Tronc commun)Section 4.3 · Drug excretion and clearance
Section 16 of 27
Non-renal routes of excretion
List the non-renal routes of drug excretion and explain why biliary recycling and breast-milk excretion matter clinically.
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Why this matters
If you think excretion means urine, you will miss two things that change patient care: a drug recycled through the gut can act far longer than its urine data suggest, and a drug that passes into breast milk can reach a baby who never received a prescription. The non-renal routes also explain familiar oddities, such as a bitter taste after a tablet, a rash on sweating skin, and a warning about a medicine while a mother is breastfeeding.
What you need to know first
Section 3.3 established that phase II conjugation makes drugs more water-soluble. This section follows those conjugates when they are too large for urine, using the simple idea that a drug moves between fluids along a concentration gradient.
Words to know (5)
Biliary excretion
Active transfer of drug from the liver into bile, important for large molecules and for conjugated metabolites. A glucuronide above about 400–500 daltons is preferentially excreted in bile.
Enterohepatic recirculation
The cycle in which a biliary conjugate is hydrolysed by gut bacteria, the free drug is reabsorbed and returned to the liver, prolonging its stay in the body. Oral contraceptives are recycled this way, which helps sustain a steady effect.
Glucuronidase
An enzyme produced by gut bacteria that splits the bond between a drug and glucuronic acid, releasing the free drug. Bacterial glucuronidase in the small intestine frees a conjugated drug for reabsorption.
Pulmonary excretion
Removal of gases and volatile substances through the lungs in the exhaled air. Alcohols that are highly soluble in blood and tissues are excreted mainly by the lungs.
Mammary excretion
Passage of unionised lipid-soluble drug into breast milk, where it can reach a breastfed infant. Tetracycline excreted in milk can discolour the infant’s developing teeth.
One idea at a timeIdea 1 / 6
In one sentence Excretion removes drug and metabolites through renal and non-renal routes, and the non-renal routes matter even when they carry less.
The kidney is the main route, but not the only one
The notes classify the routes of drug excretion broadly as renal, which is the major route, and non-renal. The non-renal group includes gastrointestinal and biliary excretion, the lungs, saliva, breast milk and the skin. For most drugs the kidney removes the largest share. The other routes matter for three reasons: they explain the full fate of a dose, they can prolong or shorten drug action, and they can carry a drug to a place where it affects a second person — most obviously a breastfed infant. Thinking of the body as having several exits prevents the common error of watching only the urine. A drug that is absent from urine has not necessarily been metabolised to nothing; it may have left by another door, or it may still be cycling inside the body.
For example
A volatile anaesthetic is removed largely by the lungs, a glucuronide conjugate is pumped into bile, and a lipid-soluble drug can enter breast milk; urine data alone would miss all three.
Pause and check yourself
Name four non-renal routes of drug excretion.
Show the answer
Gastrointestinal and biliary excretion, pulmonary excretion of gases and volatiles, salivary and mammary excretion, and excretion through the skin and sweat.
Read detailed explanations
Bile as a selective exit: size, charge and conjugation
The biliary route is not a passive overflow; it is a selected door. The liver uses active transport to move anions and cations into bile, so charged molecules that would never cross a membrane by diffusion can still be expelled this way. Molecular size sets the preference: compounds above roughly 400–500 daltons are preferentially excreted in bile, while smaller polar conjugates are small enough to leave in urine. Conjugation therefore does double duty. Glucuronic acid and glutathione add mass and charge at the same time, which is exactly the combination the biliary carrier system recognises, and this explains why phase II products are so prominent among biliary-excreted drugs. Once in the intestine, the conjugate faces a second decision. If gut bacteria hydrolyse the bond, the free drug is released and can be reabsorbed; if they do not, it continues to the faeces and is gone. The practical consequence is that bile is not always a one-way exit. A drug delivered into bile may return to the circulation and be conjugated again, so the liver and the gut can together form a loop rather than a line. This also means that conditions or treatments which change the gut flora can change how long a drug stays in the body, and it explains why the biliary route is studied alongside the metabolism of the drug rather than in isolation.
The chemistry of milk exposure: pH, lipid solubility and protein binding
Milk is not simply filtered plasma; it is a fluid with its own pH, its own protein content and its own fat. Three properties decide how much drug reaches it. The first is lipid solubility: unionised, lipid-soluble drug diffuses passively into milk, while a charged or very water-soluble molecule is largely excluded. The second is pH. Milk is slightly more acidic, at 6.4 to 7.6, than plasma at about 7.4, and this small difference can act as a mild ion trap for weak bases: a basic drug that crosses into milk may become charged there and be less able to diffuse back, so it can accumulate slightly. The third is protein binding. Milk contains far less protein than plasma, so a drug that travels bound in the blood has little to hold it in milk, but binding inside milk also reduces the free fraction available there. These three factors explain why a drug’s plasma level alone does not predict infant exposure. The infant’s own handling matters too: a newborn has slower metabolism and renal excretion, so a small ingested amount can produce a larger and longer effect than it would in the mother. This is why the notes single out very potent drugs, tetracycline, sulfonamides, nicotine, hypnotics, tranquillisers and opioid analgesics, as particular concerns during breastfeeding.
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Non-renal routes of drug excretion
The body seen as a set of exits. Besides the kidney, drug and metabolites leave through the gut and bile, the lungs, saliva, breast milk and the skin.
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01 / 6Gastrointestinal and biliary excretion
If the drawing is wider than this panel, scroll it sideways. Labels stay readable; the numbered explanations below show the same ideas.
Gastrointestinal and biliary excretion
Orally administered drug that is never absorbed leaves in the faeces, together with drug–drug and drug–food complexes and high polymers. The liver also pumps drug into bile, and this is an important exit for large molecules and for conjugated metabolites.
Schematic body, not to scale. The size of each exit box reflects the space needed for its label, not the fraction of drug it removes.
Key points to remember
✓Renal excretion is the major route, but non-renal routes explain the fate of a dose and can affect other people.
✓Unabsorbed drug and complexes leave in the faeces; the liver actively secretes large molecules and conjugates into bile.
✓Enterohepatic recirculation uses bacterial glucuronidase to release drug for reabsorption, prolonging half-life and action.
✓Gases and volatiles are excreted by the lungs, at a rate set by pulmonary blood flow and respiration.
✓Saliva, breast milk and sweat are minor routes that matter when a drug reaches an infant or irritates the skin.
Go deeper
Worked example
A breastfeeding mother and a tetracycline. A mother who is breastfeeding is prescribed a tetracycline antibiotic. Explain which excretion routes are relevant and what the implications are for her baby.
Identify the routes: the renal route will remove much of the drug, but tetracyclines are also excreted in breast milk, because milk pH and lipid solubility allow unionised drug to diffuse into it.
Consider the infant: a drug in milk is swallowed by a breastfed infant, so the infant is exposed to a medicine that was never prescribed for them.
Recall the specific harm: tetracyclines can discolour developing teeth, which is why excretion into milk is a clinical concern rather than a laboratory curiosity.
Compare with other examples: sulfonamides can cause jaundice through interaction with bilirubin, and hypnotics, tranquillisers and opioid analgesics can depress the infant’s central nervous system.
State the general principle: whenever a drug can pass into milk, the question is not only how the mother clears it, but how much reaches the infant and what that amount can do.
Non-renal excretion is not a footnote. When the route is breast milk, the drug reaches a second patient whose size, metabolism and stage of development change its meaning entirely.
Common misconception
Many learners assume that if a drug is not found in urine it must have been completely metabolised. It may instead have been excreted in bile, recycled through the gut, breathed out, or passed into breast milk. Absence from urine is not proof of complete metabolism.
Check your reasoning
Why does a drug that undergoes enterohepatic recirculation often need a less frequent dose than its renal clearance alone would suggest?
Reveal an answer
Because each cycle of biliary excretion and bacterial release returns drug to the circulation instead of removing it, so final elimination takes longer. The effective half-life and duration of action are longer than the renal data alone predict, which allows a longer dosing interval but also means any interruption of the cycle changes the blood level.
Where this comes from
General Pharmacology II lecture notes — Lecture 4, Drug excretion · Section 2C, non-renal routes: gastrointestinal, biliary and enterohepatic
General Pharmacology II lecture notes — Lecture 4, Drug excretion · Section 2C, pulmonary, salivary, mammary and skin excretion
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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.