By Duy Thai: www.geocities.com/d.

thai Pharmacology Semester 1 page 1 of 6

DRUG ELIMINATION

Rate of drug elimination

• Most drugs are eliminated at a rate which is proportional to their plasma concentration (at a higher plasma
concentration, the drug is eliminated quicker than at a low plasma concentration).
• This is known as 1st order elimination and is modeled by an exponential decay curve, where

• C = C0.e-kelim.t, or Where C = concentration of drug in plasma at any time

C0 = initial concentration of drug in plasma
kelim = rate of drug elimination from the plasma
• lnC = -kelim.t + lnC0
t = time

• Since it is more preferable to work with logarithms rather than natural logs, we can convert the above
formula into:
kelim × t
log C = log C 0 −
2.303

C0 lnC0

C lnC
Slope = -kelim/2.303

t1/2 Time, t Time, t

• The time taken for the plasma concentration, C, to fall to half its initial value is called the half life of the drug (t½)
• If C/C0 = ½ = e-kelim.t1/2, then
ln 2
t1 / 2 =
kelim
0.693
=
kelim

• Hence, if we know the elimination rate constant of a graph (via graphical interpretation), then we can easily work
out the half life of the drug.
• The half life of a drug can give us an indication of how long a drug will stay in the body.
• There are some drugs which are eliminated out of the body at a constant rate (i.e. independent of plasma
concentration). An example of such a drug is ethanol.
• These drugs are said to undergo zero order kinetics.

Routes of drug excretion

• Kidney
• Biliary system
• Lungs
• External secretions
• Sweat
• Milk
• By far the most important route of drug elimination from the body is via the kidney

Elimination by the kidney

• Drugs which are not metabolised by the liver rely on the kidney as the major way of removal of the drug from the
blood.
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 2 of 6

• For drugs which are metabolised, the liver modifies the drug so that it is more water soluble (more polar and less
toxic). The water soluble drug will be able to be filtered by the glomerulus and remain in the tubules rather than be
reabsorbed (because they are more polar – remember that unionised substances are more readily absorbed).
• The important processes of the kidney which are responsible for the excretion of a drug are:
• The GFR
• Tubular reabsorption
• A passive process occurring at the distal convoluted tubule
• Substances in the tubule are able to be reabsorbed into the blood (peritubular capillaries)
• The environment inside the tubule is very important in determining which drugs/substances will
be reabsorbed. Remember that unionised substances are absorbed better than ionised ones.
• The pH of the tubular fluid will determine whether or not acid or basic drugs filtered
through the glomerulus will be reabsorbed back into the blood. The normal urine pH is
in the range of 5 – 8. More on this later.
• Tubular secretion
• An active process occurring at the proximal convoluted tubule.
• Substances in the blood (peritubular capillaries) can be secreted into the tubules.
• If we rely solely on renal excretion to remove a drug, then the drug will have a very long half life in the
body (e.g. gentomycin).

Glomerular filtration rate

• Blood enters the kidney via the renal arteries. After many divisions, the afferent arteriole is formed.
• The afferent arteriole brings blood into the glomerulus, which filters the blood; what is not filtered leaves
the glomerulus via the efferent arteriole.
• The criteria which allow a drug to be filtered from the blood are:
1. Only the free drug can be filtered. By free I mean not bound to any plasma proteins.
2. Drugs with a molecular weight less than 20,000 will be filtered (albumin has a MW = 68,000)
• Some drugs are physically too large to be filtered, e.g. warfarin
3. The concentration of the drug in the plasma (a small concentration will be less readily filtered than
a larger concentration)

Tubular reabsorption
• Occurs in the distal convoluted tubule
• What determines whether a drug will be reabsorbed after it has been filtered?
1. Lipid solubility of the drug
• The more lipid soluble, the easier the drug will be able to pass through the tubular cells
and back into the peritubular capillaries.
2. pKa of the drug
• The pKa of a drug gives a measure of how strong an acid or base is.
• A very strong acid has a very low pKa
• A strong acid readily gives away its H+ so that it will be mainly in its ionised
form.
• AH A- + H+
• A very strong base has a very high pKa
• A strong base readily accepts a H+ and so will exist mainly in its ionised form.
• B + H+ BH+
• Strong acids or bases will be largely unaffected by fluctuations in urine pH, and so they
will tend to exist predominantly in an ionised form. This is good for us if these drugs are
in the tubular fluid, because they will be prevented from being reabsorbed.
• log [unionised/ionised] = pKa – pH (for acids)
• log [unionised/ionised] = pH – pKa (for bases)
• Say we have a strong acid with a pKa of 1 and a strong base with a pKa
of 15. The normal urine pH is between 5 and 8.
• At an acidic urine pH of 4,
• log [unionised/ionised] = 1 – 4 = -3 (for acids)
• log [unionised/ionised] = 4 – 15 = -11 (for bases
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 3 of 6

• As you can see, the acidic drug will have [unionised/ionised] =

10-3 and the basic drug will be 10-11. This means that more of
the drug would be present in its ionised form.
• The same calculation can be done with a basic urine pH.
• Weak acids or bases are generally more fun (by weak, I mean a pKa ≈ 5 à8) because their
ionisation state relies largely on the urine pH.
• An acidic drug in an acidic environment will tend to remain in its unionised
form, being reluctant to give away its H+. This means that if we are trying to get
rid of an acidic drug and we happen to have acidic urine, we may have some
problems.
• To get rid of an acidic drug, the urine pH should be basic.
• Likewise can be said for weakly basic drugs. A basic drug in a basic environment
will be reluctant to accept a H+ and so will tend to exist in an unionised form.
• To get rid of a basic drug, the urine pH should be acidic.

Remember the following lines

(for a base, it is just the reverse)

Acid drugs are absorbed well in acid environment

BUT…..

Acid drugs are excreted well in an alkaline urine

• The urine pH can be made acidic (to increase excretion of basic drug) by diet (eating lots
of proteins).
• The urine pH can be made basic (to increase excretion of acidic drug) by administering
NaHCO3

Tubular secretion
• Occurs at the proximal convoluted tubule
• Uses a Tm system where drugs or endogenous substances can be secreted into the tubular fluid, often against
their concentration gradient.
• The drugs and endogenous substances can share the same transporter. So too can other drugs.
• Hence, to prolong a drugs life, we can prevent it from being secreted into the tubular fluid by giving
another drug which competes for its same transporter. E.g. Probenecid competes with penicillin,
thus prolonging the life of penicillin.
• Drugs bound to plasma proteins cannot be filtered at the glomerulus, but they can be secreted.
• This occurs because as the free drugs are filtered from the blood, more of the bound drug will
dissociate and hence the “new” free drugs which missed being filtered the first time round, will be
able to be secreted.

• The extent of renal excretion varies markedly from drug to drug

• Transport processes depends on the structure of a drug and whether or not it is bound.
• The extent of renal excretion also varies form person to person, since it depends on the renal function of an
individual. Age is an important factor here since as we age, the number of functional nephrons declines.
• To calculate the renal clearance of a drug:

C u .Vu
Renal clearance =
Cp
Cu = Concentration of the drug in the urine
Vu = Urine flow rate
Cp = Concentration of the drug in plasma
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 4 of 6

• If the clearance of the drug is > GFR, then the drug has been actively secreted into the tubules
• If the clearance of the drug is < GFR, then the some of the drug has been reabsorbed
• If a drug relies heavily on the kidney for its clearance (e.g. gentomycin, digoxin), then renal function is
important and renal impairment is of utmost concern.
• Renal impairment can mean:
• Immature renal handling at birth
• Decline of renal function with age
• Renal disease
• If the drug is in very high concentrations in the kidneys, then crystallisation can occur in the tubules,
resulting in crystalluria.
• As urine flow rate increases, the extent of clearance is increased (fairly obvious)!

Biliary excretion

Excreted in faeces

Drug in bile Intestine

Reabsorbed in enterohepatic
circulation (recycled)
• How does a drug enter the bile?
• Transport systems transport the drug from the plasma into the bile against a concentration gradient
(the concentration of drug in bile > concentration in plasma).
• There are separate processes for acids, bases and uncharged conjugated forms of drugs
• It is a saturable process
• Large molecular weight drugs may be subject to this type of transport.

Lungs
• Can be used to eliminate gases and volatile anesthetics

Sweat and milk

• Drugs which are present in sweat may cause skin sensitivity
• Lactating mothers need to be aware that breast milk may contain drugs which are being taken by the
mother. These drugs may not be able to be handled by the baby

• Summary
• The elimination of a drug in the body depends if it is handled by the liver or kidney
• Need to know whether the function of either liver or kidney is compromised
• Effects of other drugs
• Their effect on the metabolism of drugs in the liver by:
• Induction of enzymes
• Inhibition of enzymes

Relative importance of metabolism and renal excretion – Systemic clearance of a drug

Clearance is: “The volume (of plasma presumably) from which all the drug is completely
removed per unit time.”
• Total clearance = sum of the individual clearances
= renal clearance + organ clearance
• Renal clearance has already been considered
• Organ clearance (e.g. by the liver)

CA CV
Organ
Q = flow of blood Q = flow of blood
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 5 of 6

Some drug eliminated

• Organ clearance is essentially measuring the amount/concentration of drug entering an organ and
then measuring the amount/concentration leaving the organ. Usually, the amount/concentration
leaving the organ is less because a certain fraction has been cleared by the organ.
• Note that amount is equal to the concentration × volume (or flow, if we want a rate)
• We calculate the extraction ratio as being:

Drug concentration in arterial blood - Drug concentration in venous blood

ER =
Drug concentration in arterial blood
(C A − C V )
=
CA

• The extraction ratio tells us how efficient an organ eliminates a drug.

• The rate of elimination is the amount (i.e. mass) of drug cleared from the plasma per minute.
• It is: Rate of elimination = Q.CA – Q.CV
NB:
C = concentration = grams/ml
• The clearance of an organ is: Q = flow = ml/min

Therefore if C × Q, then:
Q(C A − CV ) C(Grams/ml) × Q(ml/min) = grams/min
• Cl =
CA = amount of drug per minute

• The total body clearance (systemic clearance) is the sum of the renal clearance and the organ clearance.
• You can work out the organ clearance and then the renal clearance and add the 2 together to give
you the total clearance of the drug.
• An alternative way is to use this simple formula:
Cls = Volume of distribution × elimination rate constant
= Vd × kelim
• This only works for a one compartment model (1st order kinetics)

renal clearance
• Fraction excreted unchanged =
Total clearance
hepatic clearance
• Fraction metabolised =
Total clearance
• e.g. The following data was obtained for a particular drug:

Total clearance (L/hr) 3

Vd (L) 25
Fraction excreted unchanged 0.1
Liver blood flow (L/hr) 90

• To calculate renal clearance:

renal clearance
• 0.1 = ∴renal clearance = 0.1 × 3 = 0.3
3
• To calculate hepatic clearance
• Hepatic clearance = total clearance – renal clearance
= 3 – 0.3
= 2.7
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 6 of 6

Repeated drug doses

Toxic level of drug

Minimum effective level of

drug

• If a drug is administered by slow infusion directly into the circulation, the concentration of the drug in the
plasma will rise in a slow curve until it reaches a plateau, after which the drug concentration will decline in
an exponential decay curve.
• If the drug is not administered continuously in a slow infusion, but given repeated doses, the concentrations
of the drug in the body will fluctuate much more, although the mean will still be essentially the same as the
continuous infusion.
• If the drug was given twice daily, then the maximum dosage will be much smaller than if the drug
was given once daily. Why? Because if the drug was given once daily, more of it will have been
eliminated between injections.
• However, you can see that sometimes the drug concentrations will drop below the minimum
effective level, and so the drugs will have no effect. More importantly, we need to consider that no
all of the drug will have been eliminated from the previous injection, and so any subsequent
injection will add to the concentration of drug still present. This will result in concentrations of
drug which will be higher than the toxic level, causing much harm.
• Drugs such as digitoxin, which has a toxic level very near to its therapeutic level, need to have the
concentration monitored very closely, because there is little margin for error.

• Sometimes a loading dose is given where a large bolus of drug is given to the desired concentration very
quickly and maintained at that level.