FAR370

Pharmacokinetics

Lecturer: Machel Leuschner

1
 OVERALL OUTCOMES

• Pharmacokinetic parameters
• Discuss how absorption parameters
influence pharmacotherapy
• Discuss how distribution parameters
influence pharmacotherapy
• Discuss how metabolism parameters
influence pharmacotherapy
• Discuss how excretion parameters
influence pharmacotherapy

2
Source:Basic and Clinical Pharmacology 14th ed. Bertram. G. Katzung 3
PHARMACOKINETIC
PRINCIPLES

4
 ASSESSMENT OUTCOMES
• Describe and discuss the PK principles,
influencing factors and clinical importance of:
• Half-life
• Cmax, MEC, Steady state concentration
• Order kinetics
• Vd
• Calculate plasma concentration & steady
state
• Zero and 1st order kinetics
• Interpret and draw PK profile given relative
information

5
PK PRINCIPLES
• 'What the body does to the
medicine’
• Rate and extent of absorption
and distribution
• Rate and pathways by which
medicines are eliminated
(metabolism and excretion)
• Relationship between time and
Pharmacokinetics (PK) is the study of plasma medicine concentration.
how the body interacts with
administered substances for the entire
duration of exposure ADME
Source: https://www.pharmacologyeducation.org/ clinical-pharmacology
6
Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 7
 STEADY STATE
• Implies a stable plasma
medicine level (Cpss)
• medicine input = medicine
output
• medicine clearance and
elimination is a constant
process = thus true steady-
state only occurs following
constant iv infusion

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 9
PK PRINCIPLES – ORDER KINETICS
Clearance and Volume of Distribution (VD)
The assumptions being made with this concept are:
• Elimination is first order
• medicine is rapidly distributed. The body acts as a single
homogenous compartment.

Vd determines the distribution of drugs between the blood and the

rest of the body.

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PK PRINCIPLES – ORDER KINETICS

First order - The elimination rate

is directly proportional to
concentration (fixed fraction)
One compartment model
• Distributes of medicine into body
immediately after its appearance
in the blood
• Concentration in blood directly
reflects the concentration in all
organs and tissues

Source:A Textbook of Clinical Pharmacology and Therapeutics, 5th ed. 11

PK PRINCIPLES – ORDER KINETICS

First-order kinetics
Most medicines, the amount of medicine
metabolized per unit time is proportional
to the plasma concentration of the
medicine (Cp) and the fraction removed
is constant

Zero-order kinetics.
Some medicines, metabolic capacity is
saturated and medicine metabolism
becomes zero order; that is, a constant
amount of medicine is metabolized per
unit time.

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DISTRIBUTION AND ELIMINATION
MODELLING

Source:Basic and Clinical Pharmacology 14th ed. Bertram. G. Katzung 13

VOLUME OF DISTRIBUTION

Simple Container Model | Interactive Clinical Pharmacology (icp.org.nz)

• The apparent volume into which a medicine distributes in the body at

equilibrium is called the volume of distribution.
• The volume is not a real volume but a figure that gives us the theoretical
size of the compartment that would be needed if all the medicine in the
body was present at the same concentration as is measured in the
sample.
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VOLUME OF DISTRIBUTION

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VOLUME OF DISTRIBUTION

Low Vd(<15 L)
• Mostly confined to systemic circulation
• Higher Cp
• Faster metabolism/ elimination e.g.
penicillin
High Vd(>40 Vd)
• Spread throughout the body
• Lower Cp
• Slower metabolism/elimination e.g.
tricyclic antidepressants

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PK PRINCIPLES - VD

• If the Vd calculated is similar to the total body fluid volume, it means that
the medicine is found mainly in those fluids
• For digoxin; Vd is 400-600 L, which is approximately 10 times the
volume of total body fluids, for a 70 kg man – this means simply that the
medicine is extensively distributed outside vascular tissue, in this case,
it is bound to muscle tissue

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PK PRINCIPLES - VD

Measure of drug’s distribution in the body

Theoretical volume (in L) into which administered drug has to be
dissolved to yield plasma concentration (Cp)
– No reference to actual volume of body or its fluids
– Indication of lipophilicity and plasma protein binding
– Inverse relationship between Vd and Cp
– Direct relationship between Vd and half-life (t½)
– Used to determine loading dose (larger dose than maintenance
dose) for initial or emergency treatment

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 ABSORPTION
Influence of absorption parameters on
pharmacotherapy

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 ASSESSMENT OUTCOMES
• Describe the principle of absorption
• Compare passive and active transport
mechanisms & influence of different
physicochemical factors
• Describe the ionisation status, solubility
and permeability of medicines in different
pH ranges & the importance of pH
partitioning
• Discuss factors which influence facilitators
in transport
• Describe bioavailability and its affecting
factors & clinical relevance
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PRINCIPLES OF ABSORPTION

Process by which a medicine proceeds from the site of administration to

the bloodstream (site of measurement within the body) , across biological
membranes

Absorption affects … of action

• Onset
• Duration
• Intensity
Transport classified according to energy dependency
–Passive (does not require energy) – WITH concentration gradient
–Active (requires energy) – AGAINST concentration gradient
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 PASSIVE AND ACTIVE TRANSPORT

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 22
 PASSIVE TRANSPORT
(SIMPLE DIFFUSION)

Direct movement of drug through semi-permeable membrane until

equilibrium reached
–Along concentration gradient
–No cellular energy used

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 23
 PASSIVE TRANSPORT
(PHYSICOCHEMICAL FACTORS AFFECTING SIMPLE DIFFUSION)

• Solubility
Lipophilic molecules pass through lipid bilayers more easily than
hydrophilic molecules
• Size
Small, low-molecular weight molecules pass through lipid bilayer
more easily than large ones
• Ionisation
Ionisation state alters solubility of compounds – unionised molecule
cross lipid membrane more readily

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 24
 IONISATION STATUS & PERMEABILITY

Henderson-Hasselbalch equation: the fraction unionised or

ionised is only defined by the pH of the medicine-dissolving medium
and the pKa of the medicine.
Unionised medicine molecule
crosses lipid biological
barriers (membranes) better
than ionised medicine

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 25
 IONISATION STATUS & PERMEABILITY

Source: Dr Werner Cordier 26

 IONISATION STATUS & PERMEABILITY

Source: Dr Werner Cordier 27

PASSIVE TRANSPORT
(SOLUBILITY AFFECTS PASSIVE DIFFUSION)

Lipophilic Hydrophilic
Dissolve easily in lipids Dissolve easily in water due to
• Cross lipid bilayers freely hydrogen bonds
• Generally higher permeation into cells • Cannot dissolve in lipophilic
• Needs to dissolve slightly in water to be compartments
absorbed • Does not pass through lipophilic
Otherwise cannot pass through hydrophilic tails
heads • Reduced absorption

NB : Extremely lipophilic molecules

Cannot dissolve in aqueous compartments
Reduced absorption
28
 PASSIVE TRANSPORT
(FACILITATED DIFFUSION)

Drug molecule transported across bilayer

–Along concentration gradient
–No cellular energy used
–Facilitators (carriers/transporters) required

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 29
 FACILITATORS IN TRANSPORT

Human Efflux Model | Interactive Clinical Pharmacology (icp.org.nz)

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 30
 ACTIVE TRANSPORT

Drug molecule penetrates lipid bilayer

–Against concentration gradient - from low to high concentration
–Cellular energy (ATP) used
–Facilitators (carriers/transporters) required

Two types classified by usage of cellular energy

–Primary (direct usage of ATP)
–Secondary (indirect usage of ATP)

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 31
 ACTIVE TRANSPORT (PRIMARY)

Direct ATP usage for transport of

molecules

• ATP binds to receptor

• ATP converted to ADP, releases energy for
transport

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 32
 ACTIVE TRANSPORT (SECONDARY)

Transport occurs via electrochemical

gradient established by primary
transport (if ions transported)
• Molecule transported along with ions
against gradient
• (indirectly uses energy)

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 33
 ACTIVE TRANSPORT

Specific towards molecule

–Only specific structures recognised

Saturable system
–Finite amount of facilitators
–Transported if facilitators available
–If none available, no transport occurs until available and causes bottleneck

Types of drugs transported

–Non-diffusible or hydrophilic

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 34
BIOAVAILABILITY (F)
Fraction of administered dose which reaches the systemic circulation of the
patient.
• It reflects the rate and extent of absorption.
• Factors which can alter the bioavailability include:
• Inherent dissolution and absorption characteristics of the administered
chemical form (eg salt, ester)
• The dosage form (eg tablet, capsule)
• Route of administration
• The stability of the active ingredient in the gastrointestinal tract
• The extent of medicine metabolism before reaching the systemic
circulation – First-pass metabolism

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BIOAVAILABILITY (F)

• The bioavailability factor denoted

F, ranges from 0-1.
• One = complete bioavailability –
The bioavailability of IV
administered medicines is
usually considered to be 1.
• Oral solutions generally have a
greater bioavailability than tablets

Source:A Textbook of Clinical Pharmacology and

Therapeutics, 5th ed. 36
BIOAVAILABILITY

Source: A Textbook of Clinical Pharmacology and Therapeutics, 5th ed. 37

BIOAVAILABILITY
Medicines can be metabolised by:
• Gastrointestinal bacteria
• Gastrointestinal mucosa
• Liver, before reaching the systemic circulation

Bioavailability does not infer the strength of a drug

• Only measures amount of unchanged drug available after absorption into the
systemic compartment, NOT its activity
• Pro-drugs only active once metabolized or activated, so needs to be changed
to be therapeutically useful
Importance of bioavailability
• Dosage needed to be effective
• Changes that may occur if bioavailability altered due to disease or
interactions

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 DISTRIBUTION
Influence of distribution parameters on
pharmacotherapy

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ASSESSMENT OUTCOMES
• Describe the principle of distribution
• Discuss the factors that influence
• plasma protein binding,
• body-fat partitioning, and
• blood-brain barrier permeability & its
clinical relevance
• Explain how body fat partitioning may
alter medicine distribution and excretion

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DISTRIBUTION

• Process of movement of a medicine around the body,

from the bloodstream to tissues and organs
• Two aspects of distribution
• Rate - How fast the medicine is distributed (rapid (within
minutes, moderate (1-2 hours), or slow (>6 hours) THUS:
Time following administration before any serum level
obtained can be correlated with the concentration in the
area where the medicine is actually active
• Extent - Concentration achieved after distribution is
complete
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 PRINCIPLES OF DISTRIBUTION

The fraction of free medicine (α)

α = free medicine concentration

total medicine concentration

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 42
DISTRIBUTION

Distribution into interstitial and intracellular fluids influenced by:

• Physicochemical properties of the medicine
• Rate of deliver to target organs (cardiac output, regional blood flow,
capillary permeability, tissue volume)
Widespread, organ-specific or localised
• Spreads to major fluid compartments of the body - Circulatory system is
the first compartment to which distribution occurs
• Plasma (circulatory fluid)
• Interstitial fluid (fluid between cells)
• Intracellular fluid (fluid in cells)
• Capacity of different compartments to interact with the medicine

43
Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 44
PLASMA-PROTEIN BINDING

Protein Binding | Interactive Clinical Pharmacology (icp.org.nz)

Drug dissolves in plasma and/or binds to plasma proteins

Plasma proteins in blood
• Albumin
• Lipoproteins
• Acid glycoprotein
• α, β and γ-globulin

Function of albumin
– Maintains colloidal osmotic pressure of blood
– Carrier for hydrophobic molecules
– Drug/molecule binding
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PLASMA-PROTEIN BINDING
• Medicines circulate in bloodstream bound to plasma proteins -
binding is usually reversible.
• Albumin is a major carrier for acidic medicines;
• α1-acid glycoprotein binds basic medicines;
• Nonspecific binding to other plasma proteins;
• Certain medicines may bind to proteins that function as
specific hormone carrier proteins
• binding of estrogen or testosterone to sex hormone–
binding globulin
• binding of thyroid hormone to thyroxin-binding globulin

46
PLASMA-PROTEIN BINDING
Fraction of total medicine in plasma that is bound is determined by:
• Medicine concentration
• Affinity of binding sites for the medicine
• Concentration of available binding sites
• Disease related factors (hypoalbuminemia)
• Disease states and medicine-medicine interactions (high-clearance
medicines of narrow therapeutic index that are administered
intravenously, such as lidocaine)

47
TRANSPORT IN CIRCULATORY SYSTEM
(PLASMA PROTEIN BINDING: FREE AND BOUND)

Source: Illustration by Prof Werner Cordier 48

 PLASMA-PROTEIN BINDING

• Measured concentrations of medicine in plasma often

misinterpreted - assays do not distinguish free medicine from
bound medicine
• Binding of a medicine to plasma proteins limits concentration in
tissues and at its site of action - only unbound medicine is in
equilibrium across membranes
• Binding of a medicine to plasma protein limits glomerular filtration
and may also limit medicine transport and metabolism

49
TRANSPORT IN CIRCULATORY SYSTEM
(DIFFERENCES BETWEEN FREE AND BOUND)

Free fraction pharmacologically Bound fraction pharmacologically

active inert - Systematically released as
free fraction
No biological effect because cannot fit
Elicits biological effect
into active sites of drug targets
Transported across cellular systems Does not get transported
Gets metabolised Does not get metabolised
Gets excreted Is not excreted and not filtered by kidney

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TRANSPORT IN CIRCULATORY SYSTEM
(CLINICAL IMPLICATIONS OF PLASMA PROTEIN)

Plasma protein-bound drugs have clinical implications

–If highly bound, free fraction is decreased
–If plasma proteins saturated or depleted, free fraction is increased
–Drug displacement may occur during drug interactions

51
BODY FAT PARTITIONING
Medicine accumulate in tissues at higher concentrations than in extracellular
fluids and blood – reservoir to prolong action
• Tissue binding occurs with cellular constituents - reversibly
• proteins,
• phospholipids, or
• nuclear proteins
• Large fraction of medicine in the body may be bound
• Can produce local toxicity (e.g., renal and ototoxicity associated with
aminoglycoside antibiotics)
• Lipid-soluble medicines stored by physical solution fat -
stable reservoir (low blood flow) -
obese vs lean
52
BODY FAT PARTITIONING
Body fat consists of a large, non-polar compartment with a poor blood
supply

Drug accumulation into body fat

– Only drugs with high lipophilicity accumulate easily
– Chronic administration of lipophilic drugs (e.g. anaesthetics), or those with
low metabolic clearance, may accumulate
– Important in obese patients
– Explains lasting toxicity of several lipophilic drugs

53
BLOOD BRAIN BARRIER PERMEABILITY
• Brain capillary endothelial cells - continuous tight junctions
• Protective barrier between blood supply and central nervous
system - Prevents toxin entry into brain
• Medicine penetration into the brain depends on transport
• The more lipophilic a medicine, the more likely to cross the BBB
• In general, the BBB’s function is well maintained
• Meningeal and encephalic inflammation increase local permeability
• Medicines also imported to and exported from the CNS by specific
transporters

54
BLOOD BRAIN BARRIER PERMEABILITY
(TRANSPORT ACROSS BLOOD-BRAIN BARRIER)

55
 FACILITATORS IN TRANSPORT

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 56
 METABOLISM
Influence of metabolism parameters on
pharmacotherapy

57
ASSESSMENT OUTCOMES
• Describe the principle of metabolism
• Differentiate between
• phase I and II metabolism, and
• induction and inhibition of metabolism
• Discuss factors which influence the
metabolism of medicines
• Describe first-pass metabolism (process,
enzyme systems and implications)
• Discuss the clinical outcomes of
metabolism and first-pass metabolism

58
PRINCIPLES OF METABOLISM
Chemical conversionof substrates to metabolites

Metabolism of drugs by enzymes

– Body’s detoxification process of molecules
– Increases hydrophilicity to allow for the removal of unwanted chemicals in
urine
– Occurs mainly in liver, but also intestines, plasma, lungs
– Can be catabolic (break-down) or anabolic (build-up)
– Controlled by various enzymes, such as the CYP450 enzymes

59
PRINCIPLES OF METABOLISM

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METABOLISM
(APPROXIMATE % DRUGS METABOLISM BY CYP450)

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PRINCIPLES OF METABOLISM
• A medicine pass through the body
• unchanged, or
• metabolised to some other substance
• The metabolite can be either active/inactive
• The metabolite may also be more water soluble than the
administered medicine, so that it is excreted more rapidly
• Some medicines (pro-medicines) have to be metabolised to
yield an active moiety
• Hepatic smooth endoplasmic reticulum – CYP450 enzymes

62
PRINCIPLES OF METABOLISM
General Principle | Interactive Clinical
Pharmacology (icp.org.nz)

Cp-time Effect | Interactive Clinical

Pharmacology (icp.org.nz)

63
PHASE I AND PHASE II METABOLISM

oxidation,
reduction and
hydrolysis.

Source:Basic and Clinical Pharmacology 14th ed. Bertram. G. Katzung 64

PHASE I AND PHASE II METABOLISM

Source:Basic and Clinical Pharmacology 14th ed. Bertram. G. Katzung 65

PHASE I AND PHASE II METABOLISM

Different phases through which drugs are metabolised, but not necessarily
in a systematic process

66
 INDUCTION & INHIBITION OF METABOLISM

- An enzyme inducer is a - An enzyme inhibitor is a

drug which drug which
• Induces liver enzymes • Inhibits liver enzymes
• Increase the rate of • Affects the optimal level of
metabolism metabolism
• Reduce the effectiveness • Increase concentration
of concomitantly (and possibly toxicity) of
administered drugs concomitantly
administered drugs
Pharmacokinetic | Interactive Clinical Pharmacology (icp.org.nz)
67
68
PRINCIPLES OF METABOLISM

69
PRINCIPLES OF METABOLISM

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FIRST PASS METABOLISM

Sum of all metabolic effects in GIT and liver that reduce Cp of drug
before reaching systemic circulation

Blood flow to the systemic circulation

– Blood flow from intestines first goes to the liver
– After liver, distributed to the rest of the systemic circulation

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 Elimination
Influence of elimination parameters on
pharmacotherapy

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ASSESSMENT OUTCOMES
• Describe the principle of excretion
• Describe the excretion pathways most
relevant to medicines
• Describe the relevance of renal and
biliary clearance
• Discuss the factors that influence renal
and biliary clearance, as well as the
clinical importance thereof

73
PRINCIPLES OF EXCRETION

Removal of drug or metabolites through excretory organs

Main routes of excretion

– Kidneys (as urine) – Primary excretion route
– Hepatobiliary system (as bile and faecal matter)
– Lungs (as volatile gasses)

Negligible excretion routes

– Milk, tears, saliva, semen and sweat
– May be important for side effects
74
PRINCIPLES OF EXCRETION

The elimination of a medicine is referred to as its clearance

• Total medicine clearance is the sum of all the various
clearances, e.g urinary, pulmonary, biliary etc.

Human Model | Interactive Clinical Pharmacology (icp.org.nz)

75
PRINCIPLES OF EXCRETION

• Medicine clearance is reported as units of plasma (or blood)

cleared per unit time
• Thus it is a proportionality constant that relates the rate of
elimination to the concentration. The relationship is shown
simply by the equation;

Rate of elimination (Ro) = clearance (CI) x plasma

concentration (Cp)

76
PRINCIPLES OF EXCRETION

Two major sites of drug elimination

• Kidneys
• Liver
Clearance of unchanged drug in the urine = renal clearance.
Within the liver, drug elimination occurs via biotransformation
of parent drug to one or more metabolites, or excretion of
unchanged drug into the bile, or both.

77
PRINCIPLES OF EXCRETION

• Small Vd with a high clearance = medicine is removed rapidly

• Large Vd with a small clearance = medicine is removed slowly
• How long significant amounts of medicine remain in the system
depends on both the volume of distribution and the clearance

K = Cl
Vd

K = elimination rate constant

Cl = clearance
Vd = Volume of distribution
78
79
RENAL CLEARANCE

Creatinine clearance is used

as a measure of the
glomerular filtration rate

81
82
RENAL CLEARANCE

Source:A Textbook of Clinical Pharmacology and Therapeutics, 5th ed. 83

 FACILITATORS IN TRANSPORT

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 84
 BILIARY CLEARANCE

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 86
 BILIARY CLEARANCE
Large, charged or amphipathic drugs may be excreted by hepatocytes into
duodenum

Drugs excreted in bile

– Usually hydrophilic phase II conjugates, mainly glucoronides
– Eventually excreted as faecal matter

Mechanisms underlying biliary excretion

– Passive diffusion
– Facilitated diffusion and active transport

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 87
 HALF-LIFE (T½ - CLINICAL IMPLICATIONS)

Drugs with short t½ – Steady state achieved earlier

Drugs with long t½ – Steady state achieved later

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 88
 ZERO ORDER KINETICS
Undergoes linear decline
– Few drugs (e.g. phenytoin, alcohol)
– Saturable parameters (e.g. enzymes, transporters)
ADME processes are rate-limiting factors –Will be cleared completely after
enough time

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 89
 FIRST ORDER KINETICS

Undergoes exponential decline

– Most drugs follow first-order kinetics
– In normal circumstances, drug
accumulation will not occur
– Predictable profiles
– Drug will in essence not be cleared
fully, but reaches low enough
concentration to be ‘essentially
gone’

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 90