Drug excretion

Excretion is the process whereby

compounds are removed from the body to the
external environment.
Routes of drug excretion
Removal of a drug from the body may occur via
a number of routes:
- Kidneys (urine)
- The intestinal tract (bile and feces)
- The lungs (exhaled air)
- Breast milk (in nursing mother)
- Sweat
Excretions in the urine and feces are the most
important routes of drug elimination.
 Excretory organs, the lung excluded,
eliminate polar compounds more efficiently
than substances with high lipid solubility. Lipid-
soluble drugs thus are not readily eliminated
until they are metabolized to more polar
compounds.
The kidney is the most important organ for
excreting drugs and their metabolites.
Substances excreted in the feces are
principally unabsorbed orally ingested drugs or
drug metabolites excreted either in the bile or
secreted directly into the intestinal tract and
not reabsorbed. Conjugation, particularly with
glucuronic acid, facilitates biliary excretion.
 Excretion of drugs in breast milk is
important not because of the amounts
eliminated, but because the excreted drugs are
potential sources of unwanted pharmacological
effects in the nursing infant.
Excretion from the lung is important
mainly for the elimination of anesthetic gases
or volatile materials.

Fig: Bile duct

Renal elimination of a drug
The kidney:
Plays significant role in regulating volume
and composition of body fluids.
Conserves essential substances and
removes waste products.
Removes H2O soluble drugs & metabolites
from body.
Excretion of drugs and metabolites in the
urine involves three distinct processes:
Glomerular filtration
Proximal tubular secretion
Distal tubular reabsorption
Glomerular filtration:
Drugs enter the kidney through renal
arteries (afferent arterioles), which divide to
form a glomerular capillary plexus. Free drug
(not bound to protein and RBC) flows through
the capillary slits into Bowman's space as part
of the glomerular filtrate.
The glomerular filtration rate
(GFR=125ml/min) is normally about 20% of the
renal plasma flow (RPF =650ml/min).
Lipid solubility and pH do not influence the
passage of drugs into the glomerular filtrate.
Low molecular weight compounds (<60,000
dalton) filtered from blood.
Warfarin is approximately 98% bound to
albumin (molecular weight approximately
68,000 dalton), the concentration in the
glomerular filtrate is only 2% of that in plasma,
and clearance of this drug by filtration is thus
correspondingly reduced.
Proximal tubular secretion:
Drug that was not transferred into the
glomerular filtrate leaves the glomeruli through
efferent arterioles, which divide to form a
capillary plexus surrounding the nephric lumen
in the proximal tubule.

Secretion primarily occurs in the proximal

tubules by two energy-requiring active
transport systems, one for anions (for example,
deprotonated forms of weak acids) and one for
cations (protonated forms of weak bases).
- Most effective mechanism
- Reduces plasma drug concentration nearly to
zero
Active secretion of both free & protein-bound
drug by transporters:

Anions: indomethacine, urate, penicillin,

glucuronic acid conjugates, gluycine
conjugates, & sulphate conjugates (acidic
compounds)
Cations: morphine, choline, histamine (basic
compounds)
 Penicillin, about 80% penicillin remain as
protein-bound form and therefore cleared only
slowly by filtration, is almost completely
removed by proximal tubular secretion, and its
overall rate of elimination is very high.

Many drugs compete for the same

transport system, leading to drug interactions.
For example, probenecid was developed
originally to prolong the action of penicillin by
retarding its tubular secretion.
Distal tubular reabsorption:
As a drug moves toward the distal
convoluted tubule, its concentration increases
(as H2O reabsorbs).

In this part the drug, if uncharged (remain

lipid soluble), may diffuse out of the nephric
lumen back into the systemic circulation
(reabsorption- passive transport).
Manipulating the pH of the urine [The pH
of urine is close to neutral (7) but can normally
vary between 4.5 and 8] to increase the ionized
form of the drug in the lumen may be used to
minimize the amount of back diffusion and
hence increase the clearance of an undesirable
 A patient presenting with an acidic drug
(phenobarbital, aspirin) overdose can be given
bicarbonate, which alkalinizes the urine and
keeps the drug ionized, thereby decreasing its
reabsorption.
If the drug is a weak base
(amphetamines), acidification of the urine with
NH4Cl leads to protonation of the drug and an
increase in its clearance.
This process is called "ion trapping."

Rate of excretion = Rate of filtration +

Rate of secretion - Rate of reabsorption
Factors influencing renal drug excretion :
Gender: Female 80% renal function of males
Age: Renal function ⇓ 50% with age (25 –75 yr)
Pregnancy: Renal function ⇑ 50%
Disease: Renal disease, heart failure
Alteration of renal excretion of drugs
:1. Competitive inhibition of tubular secretion
The renal clearance of penicillin ⇓ 90% by
probenecid.

2. Influence of pH
• Sodium bicarbonate used to alkalinize urine;
ie ⇑ pH, ⇑ ionization of weak acids (salicylate,
methotrexate), ⇓ tubular reabsorption → ⇑
excretion.
• Ammonium chloride used to acidify urine to ⇑
excretion of basic drugs (amphetamines).
3. Influence of urinary flow rate
• ⇑ urinary flow rate dilutes drug conc. in tubule
→ ⇓ conc. gradient for passive reabsorption of
drug → ⇑ excretion.
• ⇓ urinary flow rate has the opposite effect.
Excretion of drugs by the kidney
- Most drugs, unless highly bound to plasma
protein, cross the glomerular filter freely.
- Many drugs, especially weak acids and weak
bases, are actively secreted into the renal tubule
and thus more rapidly excreted.
- Lipid-soluble drugs are passively reabsorbed by
diffusion across the tubule, so are not efficiently
excreted in the urine.
- Because of pH partition, weak acids are more
rapidly excreted in alkaline urine, and vice
versa.
- Several important drugs are removed
predominantly by renal excretion, and are liable
Drug clearance
Clearance is the ability of the body or its
organs of excretion (usually the kidneys and the
liver) to remove drug from blood.

Clearance is expressed as a volume per

unit of time (usually ml/min). Clearance is not
the amount of drug removed from the body.
Clearance represents the volume of blood which
is completely cleared from drug in a given
period of time.

Total clearance is the sum of clearance by

different organs like the kidneys, the liver &
others.
Clearance as through the kidneys and
metabolism in the liver are the major routes:
Clearance (total) = Clearance (hepatic) +
clearance (renal) + Clearance (others)

A decrease in the function of an organ of

elimination is most significant when that organ
serves as the primary route of drug elimination.
 KIDNEYS CLEAN
BLOOD
+ BLOOD
DRUG 30 ml/min

BLOOD LIVER CLEAN

+ BLOOD
DRUG 50 ml/min

Drug
clearance
Rate of elimination of drug
Rate of elimination is the number of mg of
drug eliminated from the body per time
(mg/min). Rate of elimination depends on the
concentration of drug in blood and clearance:

Rate of elimination (mg/min) = Plasma

drug concentration (mg/ml) x Clearance
(ml/min)
Example:
Plasma drug concentration = 10mg/ml
Clearance = 8ml/min
Rate of elimination = 80mg/min
So, The amount of drug eliminated in one