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Drug Excretion

Excretio

For medical students3 min readUpdated 2026-10-10

Excretion is the final elimination of drugs and their metabolites from the body. The kidneys and liver play the primary role in elimination, although substances can also leave the body via exhaled air, the gastrointestinal tract, and the secretions of various exocrine glands.

Primary routeMost drugs are excreted through the kidneys via filtration and secretion.

Sorting stationHepatocytes determine whether a substance is directed into bile or returned to the bloodstream.

Ion trappingIonized hydrophilic molecules cannot be reabsorbed and leave the body.

LactationBreast milk has an acidic environment, which promotes the accumulation of weak bases within it.

Mechanisms of Renal Excretion

The kidneys are the main organ of elimination. The process of blood purification consists of three physiological mechanisms:

Glomerular filtration (filtratio glomerularis). Occurs in the renal glomeruli driven by the hydrostatic pressure of the blood. The capillary endothelium and podocytes form a selective barrier that blocks molecules with a negative charge or a diameter greater than 8 nm. An important nuance: drugs bound to large plasma proteins (albumins) do not pass through this barrier, and their excretion is delayed.
Active tubular secretion (secretio activa). Occurs in the proximal tubules against a concentration gradient utilizing ATP. Transport systems for organic acids (penicillins, furosemide) and bases (morphine) function here. Unlike the glomerular filter, this mechanism can remove substances tightly bound to plasma proteins: as the free fraction is eliminated into the tubular lumen, the equilibrium shifts, and the protein complexes dissociate. Transporters have a limited capacity, so drugs can compete for them.
Tubular reabsorption (reabsorptio tubularis). Passive back-diffusion in the distal tubules. Lipophilic (non-polar) molecules easily diffuse back into the blood, whereas hydrophilic (ionized) molecules cannot cross the membrane and are excreted in the urine.

Effect of Urine pH and 'Ion Trapping'

The degree of ionization of weak acids and bases depends directly on the acidity of the medium. If a substance converts into an ionized form, it becomes hydrophilic, ceases to be reabsorbed, and is excreted.

This principle is applied in clinical practice to force diuresis during intoxications:

Weak acids (barbiturates, acetylsalicylic acid) are poorly eliminated in an acidic environment. To accelerate their elimination, the urine is alkalinized (pH increased) by intravenous administration of sodium bicarbonate.
Weak bases (alkaloids such as quinine or nicotine) are retained in the body during an alkaline reaction. For their rapid elimination, the urine is artificially acidified with ammonium chloride.

Hepatobiliary Transport and Enterohepatic Circulation

The liver eliminates drugs via a complex system of transporters. Hepatocytes uptake molecules from the sinusoids and then pump them through the canalicular membrane into the bile using ATP-dependent proteins (e.g., P-glycoprotein).

Once in the intestinal lumen with bile, a drug may enter enterohepatic circulation (circulatio enterohepatica). If the drug formed a conjugate with glucuronic acid in the liver, this bond can be hydrolyzed in the intestine. The released active lipophilic substance is reabsorbed through the intestinal wall into the portal venous system (vena portae) and returns to the liver. Such a cyclic process significantly prolongs the therapeutic effect of drugs (characteristic of morphine, ethinyl estradiol, chloramphenicol).

Drugs that are practically unabsorbed from the gastrointestinal tract (neomycin, vancomycin, nystatin) pass through the intestine in transit and are excreted in the feces, which is utilized for local treatment within the intestinal lumen.

Elimination by the Lungs and Glands

Lungs (excretio per pulmones): eliminate volatile liquids and gases. The elimination of ethanol vapors correlates directly with its plasma concentration, which is the principle behind breathalyzers.
Salivary glands: excrete predominantly lipophilic substances via passive diffusion. The concentration of certain substances (paracetamol, lithium salts) in saliva may be higher than in plasma (concentration phenomenon). Due to the direct correlation with plasma concentration, saliva is often used for therapeutic drug monitoring.
Mammary glands: the process occurs during lactation. Because breast milk has a lower pH (approx. 6.5) than blood plasma (7.4), weak bases (benzodiazepines, nicotine) actively accumulate in it via the 'ion trapping' principle. Lipophilic drugs also actively penetrate milk due to the lipid fraction, creating a risk of allergic and toxic reactions in the infant (cytostatics and isoniazid are strictly contraindicated).

Mnemonic

To remember how to accelerate elimination in poisonings, use the rule of opposites: weak acids are actively eliminated by alkali, and weak bases by acid. The key is to convert the substance into its ionized form.

Frequently asked questions

What are the main pharmacokinetic parameters of excretion, including half-life and total clearance?

Quantitative parameters of elimination include the elimination rate constant (Kelim), half-life (t½), and total clearance (ClT).

Half-life (t½) — the time required for the plasma concentration of a drug to decrease by half.
Total clearance (ClT) — an indicator of the body's ability to clear the drug; it is used to individually calculate the maintenance dose.

What is the role of SLC and ABC family transporters in renal and hepatic drug excretion?

Transporters of the SLC and ABC families provide directional transport of drugs during their elimination by the liver and kidneys.

Organ	Role of SLC Transporters	Role of ABC Transporters
Liver	Mediate the uptake of molecules from blood into the hepatocyte across the sinusoidal membrane.	Mediate ATP-dependent efflux of substances into bile across the canalicular membrane.
Kidneys	Transport hydrophilic and lipophilic ions across the basolateral and apical membranes of epithelial cells.	Pump drug conjugates out of the cell into the renal tubular lumen.

Which renal and hepatic pathologies significantly affect drug dosage adjustments?

Impaired renal and hepatic function can necessitate drug dosage adjustments, particularly for drugs whose elimination or metabolism depends on these organs.

Renal impairment: decreased glomerular filtration can lead to the accumulation of drugs predominantly excreted by the kidneys, requiring dose adjustment. For diethylcarbamazine, reduced renal function requires a lower dosage to avoid accumulation and toxicity.
Liver disease: for drugs metabolized primarily in the liver, reduced metabolic capacity requires a lower dose.
Decreased hepatic blood flow: elderly patients or those with chronic heart failure may require a reduced dose of lipophilic beta-blockers.
In liver or kidney pathology, relative overdose may occur due to impaired metabolism or excretion.

Why are substances bound to plasma proteins not filtered in the renal glomeruli?

The filtration barrier in the kidneys blocks large molecules with a diameter greater than 8 nm and negatively charged compounds. Because albumins are large and negatively charged, drug-protein complexes remain in the bloodstream.

How can a drug be eliminated if it is almost completely bound to plasma proteins?

Such drugs are eliminated via active tubular secretion. As the free fraction is transferred into the primary urine, the equilibrium in plasma is disrupted, and the drug dissociates from the protein, becoming available for excretion.

Why is probenecid sometimes used during penicillin therapy?

Both substances are secreted in the proximal tubules via the same organic acid transporters. Probenecid competes for the transporter, thereby slowing down penicillin elimination and prolonging its duration of action.

Go deeper

Clinical significance of genetic polymorphism of hepatic transporters (using OATP1B1 and statins as an example).
Structural features and localization of SLC and ABC transporters in tubular epithelial cells.
The phenomenon of drug recirculation during excretion by exocrine glands of the gastrointestinal tract.
Influence of plasma protein binding degree on drug penetration into breast milk.