Clearance, Volume of Distribution, and Constant Rate of Elimination

Clearance,
Volume of
Distribution
and
Elimination
Dr Rafael Venson
Rafael.Venson@Glasgow.ac.uk
MED5129 Drug Disposition
Aims and intended learning
outcomes (ILOs)
• Aim - this session will describe the elimination processes of drugs
• ILOs - by the end of this session, you should be able to apply the
relationships between:
• Clearance (), dosing rate (), average steady state concentrations ()
• Target concentration (), volume of distribution () and loading dose ()
• Elimination rate constant () and elimination half-life ()
ADME: general aspects
Absorption Distribution
• Bioavailability () • Volume of distribution ()
• Absorption rate ()
The apparent volume into which the
drug distributes within the body
Elimination: Metabolism +
Excretion
• Clearance ()
• Elimination rate constant ()
• Elimination half-life of drug ()
• Metabolism: important interpatient
source or variability in drug response
Distribution: introduction
• Drug distribution is the reversible process of transfer of the drug from
the site of absorption to the systemic circulation and to the tissues.
• Drug distribution is determined by:

• How well tissues are perfused by blood
• Drug binding to plasma proteins and tissue
• Permeability of tissue membranes to the drug molecule.
• These in turn are governed by the physio-chemical properties and

chemical structures of the drug.
Distribution: volume of distribution
• is the apparent volume into which the drug distributes within the body.
• Apparent, as not a true physiologic meaning in terms of an anatomic space.

• It does not represent physiological volumes such as extracellular fluid/extracellular
water/plasma volume.
• Relates the plasma drug concentration to the total amount of drug in the
body.
• Concentrations (drug amount per unit volume) are usually measured in

plasma or serum (more often than blood).
Distribution: protein binding (1)
• Volume of distribution () is influenced by the extent of drug-protein binding.
• Drugs that are highly plasma-protein bound will have a low fraction of free unbound ()
drug in plasma:
• They do not distribute easily
• They cannot easily diffuse across cell membranes
• Their distribution is less extensive in tissues
• They have lower
• Drugs that do not bind to plasma proteins will have a greater fraction of free unbound
() drug in plasma
• They distribute easily, as diffusion across cell membranes is easier
• They have extensive distribution within tissues
• They have higher
• Both lipid solubility and protein binding of drug molecule will influence the.
Distribution: protein binding (2)
• Diseases or conditions that alter plasma/tissue protein levels can have a significant impact
on and elimination half-life of administered drugs.
• Displacement of drugs from plasma proteins - or a reduction in the availability of plasma

proteins can increase free unbound () fraction of drug,
• Increasing drug concentration, as less drug is protein bound.
• Increasing the free drug concentration reaching pharmacological target - potential for greater
pharmacological response and risk of toxic response.
• Transient increase to individual’s for that drug.
• Greater drug diffusion into tissues of eliminating organ - altered drug elimination
• Careful assessment and consideration of altered protein levels/protein binding must be

made prior to altering the drug dose regimen.
Effect of protein binding on volume of distribution:
200mg of drug X given IV; initial measured
concentration will allow to be determined
Scenario Scenario Scenario

1: 200mg 2: 200mg 3: 200mg Low
ofTissues
drug Plasma Tissues of Tissues
drug Plasma Tissues of Tissues
drug concentr
Plasma Tissues
leading leading High leading ation,
to to concentr to high
=100mg/ =200mg/ ation, =10mg/L
L L low
vs. the patient
• may vary according to:
• Patient size (weight)
• Diseases
• Lipid and water solubility of drug
• Drug binding within both tissues and plasma
• is used to determine:
• Loading dose
• Target concentration
• Elimination half-life
• Elimination rate constant
Loading dose
• It is the initial “large” dose administered to rapidly achieve a
therapeutic target concentration
• Loading dose () to achieve target concentration (, , ) can be
determined by rearrangement of the equation:
, i.e.,
or
What if there is already some drug
in the systemic circulation? (1)
If no drug is present:
Concentration
For and, :
IV:
What if there is already some drug
in the systemic circulation? (2)
If some drug is present:

Target Concentration
(e.g. 21 mg/L)
Measured Concentration
(e.g. 10 mg/L)
For and, :
IV:
Elimination
• It is the irreversible process of drug removal from the body
• It may include both metabolism and excretion
• Most drugs are eliminated by 1st order pharmacokinetics, but some

are eliminated by zero-order
• Clearance () is a measure of drug elimination from the body

• It is the volume of plasma that is cleared of drug
• Expressed as volume per unit of time (mL/min or L/h) rather than drug
amount per unit of time
Clearance (1)
• It is dependent on extraction ratio of an eliminating organ and the
blood perfusion flow rate
• Extraction ratio is the efficiency with which an organ can remove drug from
the blood
• Flow rate is the rate of drug delivery to the eliminating organ
Cin=20mg/L Eliminating organ Cout=0mg/L
In this case, elimination rate is 1

Celiminated=20mg/L
(100%)
Clearance (2)
• May be altered by physiological and pathophysiological factors
(age/weight/pregnancy or renal, cardiac or hepatic disease, drug interactions)
• Systemic clearance/Total body clearance
• Considers the body as a single drug eliminating system (or, as one compartment)
• The sum of all individual organ clearances contributing to overall drug elimination.
• Clearance may be calculated for any organ involved in removing drugs from the body.
• Kidney and liver are the most common organs involved in excretion and metabolism
and respectively.
Clearance influences a drug’s steady state concentration () that can be reached.

Creatinine clearance ()
• Creatine is the end product of muscle metabolism (breakdown of
creatine)
• It distributes into total body water
• Normal serum creatinine concentrations vary within the population and
are:
• 8-13mg/L in adult men
• 6-10mg/L in adult women
• It appears to be eliminated from the body by the kidneys
• Usually, serum creatinine production is approximately equal to creatinine
excretion. Serum creatinine levels will therefore remain constant.
𝐶𝑟𝐶𝑙
• For some drugs, and can only be determined once the patient’s
creatinine clearance is known
• Creatinine levels are dependent on an individual’s age, sex, ethnicity,
body size, and vary due to conditions/diseases
• The Cockcroft-Gault equation is used to determine a patient’s
In this equation, is 1.04 for female and 1.23 for male

vs Drug clearance
• Creatinine clearance is then used to calculate specific drugs’ clearance
• Remember all units should be in mL and min or L and h!

Steady state concentration ()
• is reached when, within one dosage interval, drug in = drug out
• For IV bolus,
• For IV infusion rate,
• For oral,
vs maintenance dose
• Rearranging the equations, maintenance dose can be calculated
• For IV bolus,
• For IV infusion rate,
• For oral,
Linear kinetics
• Immediately following administration of a single IV bolus injection of
a drug, the initial concentration achieved () will decline by a constant
proportion per unit time as the drug is eliminated from the body.
• The elimination rate constant (k)

• Is the rate of decline of concentration over time
• Depends on both clearance and volume of distribution
• Represents the fraction of drug that is eliminated with time
• If L/h and L are used, the unit for is /h or h-1

Example 1: A single 200mg IV bolus of ‘Drug-A’ is given to
a 85kg patient, with: clearance=0.04L/h*kg; volume of
distribution=0.48L/kg. What is the elimination rate
constant for this patient?
• Step 1: identify the key information provided by the scenario
• Step 2: determine the parameters essential for calculation

𝑘
• The elimination rate constant () represents the fraction of drug that is
eliminated per unit time (/h or h-1), and it is used to determine the
drug concentration at any time after administration of the dose.
• For 1st order pharmacokinetics the decline in plasma drug
concentration as the drug is eliminated from the body is exponential,
on a linear scale.
• Therefore, by using , concentration at anytime () may be calculated if
dose, , and are all known, by applying:
Example 2: Ms SW was given a single 240mg IV bolus of
‘Drug-B’, which instantaneously dispersed.
Immediately following this single IV bolus, an initial serum
concentration () of 12mg/L was measured. What is the
predicted concentration 6hours after this measurement
was taken?
vs in 1 order elimination
st
pharmacokinetics
• For 1st order elimination
pharmacokinetics,
elimination rate constant (k)
• This decline in drug
concentration vs time is
exponential when plotted
on a linear scale (previous
slide)
• If the natural log () of vs or
the data are plotted on
semi-logarithmic graph
paper, the decline is log-
linear, as shown:
Elimination half-life ()
• The time taken for the drug
concentration to fall to half of
its original value.
𝑡 h𝑎𝑙𝑓
• The time taken for the drug concentration to fall to half of its original
value.
• Depends on and
• Elimination half-life () is used to determine:

• Time to completely eliminate drug from body
• Time for the drug concentration to reach steady state
• Dosage interval
and complete elimination
1x 50% of drug eliminated
2x 75% of drug eliminated
3x 87.5% of drug eliminated
• For a single dose, the
4x 93.8% of drug eliminated
elimination half-life governs 5x 96.9% of drug eliminated
the time taken to eliminate a 6x 98.45% of drug eliminated
drug from the body 7x 99.22% of drug eliminated
• Therefore, drug elimination
occurs 5-7 half-lives after drug
is administrated.
and time to steady state concentration
()
• During multiple dosing or a constant rate infusion, the elimination half-life also governs the
time to reach steady state concentration ().
• Once the steady state concentration is reached, average drug accumulation and average drug
elimination are equal , i.e., drug entering = drug leaving
1x 50% of
2x 75% of
3x 87.5% of
4x 93.8% of
5x 96.9% of
6x 98.45% of
7x 99.22% of
Thank you
Dr Rafael Venson
Rafael.Venson@Glasgow.ac.uk
MED5129 Drug Disposition

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Clearance,

• Drug distribution is determined by:

• These in turn are governed by the physio-chemical properties and

• Apparent, as not a true physiologic meaning in terms of an anatomic space.

• Concentrations (drug amount per unit volume) are usually measured in

• Displacement of drugs from plasma proteins - or a reduction in the availability of plasma

• Careful assessment and consideration of altered protein levels/protein binding must be

Scenario Scenario Scenario

If some drug is present:

• Most drugs are eliminated by 1st order pharmacokinetics, but some

• Clearance () is a measure of drug elimination from the body

Cin=20mg/L Eliminating organ Cout=0mg/L

In this case, elimination rate is 1

Clearance influences a drug’s steady state concentration () that can be reached.

In this equation, is 1.04 for female and 1.23 for male

• Remember all units should be in mL and min or L and h!

• For IV infusion rate,

• For IV infusion rate,

• The elimination rate constant (k)

• If L/h and L are used, the unit for is /h or h-1

• Step 2: determine the parameters essential for calculation

• Elimination half-life () is used to determine:

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