Phil Rowe Reader in pharmaceutical computing School of Pharmacy

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Phil RoweReader in pharmaceutical
computingSchool of Pharmacy Chemistry
All these presentations can be downloaded
fromhttp//www.staff.livjm.ac.uk/phaprowe/then
follow 'Nurse prescribing'
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Lecture 1 Absorption, distribution, metabolism
and excretion (ADME)Pharmacokinetics
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Part 1ADME
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The three main stages in the handling of a drug
Into the body Absorption roundy,
roundy Distribution back out.
Elimination
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Absorption
The movement of the drug from it's initial point
of application into the blood stream. Absorption
does occur even with intramuscular or
sub-cutaneous dosing etc. Only route where
absorption is not required is intravenous.
(With topical use, drug may or
may not be absorbed.)
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Distribution
The movement of the drug around the body.
Muscles
Brain
Heart
Blood
Liver
Skin
Bone
Kidneys
Fat
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Elimination
Generally subdivided into Metabolism The
chemical alteration of the drug Excretion
Removal of the drug from the body, chemically
unchanged.
'Elimination' can still be used as a general term
for the removal of a drug without specifying the
mechanism.
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Metabolism

• Chemical alteration of the drug generally
  achieves two things
• Inactivation The shape and size of the
  molecule are altered and it no longer fits its
  receptor.
• Metabolites generally more easily excreted in
  urine etc than the parent drug.
• The liver is the major organ for drug metabolism.

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Metabolism
Cytochrome P450
An enzyme that is responsible for the metabolism
of a wide range of drugs. Liver is very rich in
this enzyme. Also found wherever foreign
substances are likely to enter the body. e.g.
lining of the gut. (Defence mechanism) Exists in
various different forms (e.g. CY3A4). Some
patients may lack particular forms that are
responsible for metabolising particular drugs.
They would then be unusually sensitive to such
drugs Pharmacogenomics
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Excretion
Generally in the urine, but sometimes in bile.
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Excretion or metabolism?
Aminoglycosides (eg gentamicin)Digoxin (Some
metabolism)LithiumMethotrexatePenicillins
cephalosporins
Drug
Urine
Drug
PhenytoinPropranololTheophyllineValproateWarfa
rin
Metabolite
Urine
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Part 2Pharmacokinetics
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Pharmacokinetics
Greek origin Pharmaco...kinetics drug ....
movement The movement of drugs around the
body. Pharmacokinetics is the measurement of the
rates and extents of the processes included
within ADME.
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Pharmacokinetic values
Absorption Bioavailability Distribution
Volume of distribution Elimination Half life
and clearance
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PharmacokineticsAbsorption

• Could describe
• Rate
• Extent
• of absorption.
• Rate can sometimes be important, but extent is a
  much bigger issue.

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Changing the rate of absorption
Ka 0.25h-1
Rapid
Slow
Ka 1.5h-1
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Slow release Controlled release Modified
release
Idea is to provide steady concentrations without
sudden peaks or troughs. e.g. Phyllocontin
Continus (Modified release Theophylline) Only
need be taken twice daily, whereas simple tablets
have to be taken 3 or 4 times daily
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Extent of absorption Bioavailability
Bioavailability The fraction of an administered
dose that is absorbed into the general blood
stream. e.g. If we administer 5mg of a drug
orally and 1 mg gets into the blood stream,
bioavailability 20
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Bioavailability and routes of administration
I.V. - only route where bioavailability is
guaranteed to be 100 Oral - Many potential
barriers to full bioavailability
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Incomplete oral bioavailability
2. Chemical, enzymatic or bacterial attack
4. First pass metabolism in gut wall or liver
3. Failure of absorption
Liver
1. Failure of disintegration or dissolution
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Oral bioavailability
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PharmacokineticsDistribution
What we want to describe is the movement of drug
between the blood and the tissues. Main thing to
describe is where the drug ends up. Is it mostly
in the blood or in the tissues?
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Volume of Distribution
Blood
Tissue
Stays mainly in blood. Small volume of
distribution.
Distributes evenly. Medium volume of
distribution.
Distributes strongly into tissue. Large volume
of distribution.
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Volumes of distribution(In litres for average 70
kg adult)

• Warfarin 7
• Gentamicin 16
• Theophylline 35
• Cimetidine 140
• Digoxin 510
• Mianserin 910
• Quinacrine 50,000

Small vol. Mainly stays in plasma little in
tissues.
Medium vol. Similar concs in plasma and tissues
Large vol. Mainly in tissues, little in plasma.
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Reasons for distinctive volumes of distribution
Blood
Tissue
Warfarin binds to protein (Albumin) in blood.
Stays mainly in blood. Small volume of
distribution.
Quinacrine binds to DNA in tissues. Held in
tissues. Large volume of distribution.
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PharmacokineticsElimination

• What we want to describe is the rate at which a
  drug is eliminated from the body.
• There are 2 commonly used parameters
• Half-life
• Clearance

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Half-life
The time required for a 50 reduction in blood
concentrations of drug. Half life is independent
of how high or low the initial concentration may
be.
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Half-life (t ½)
4 3 2 1 0
C0 4 mg/L
Inefficiently eliminated
Efficiently eliminated
Conc (mg/litre)
Long t ½
t ½ 2.3 h
t ½ 5.4 h
Short t ½
0 2 4 6 8 10
Time (hours)
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Half-lives (hours)Averages for healthy adults
Amoxycillin 1Cefamandole 1Cimetidine
2Propranolol 4Theophylline
9Griseofulvin 15Lithium 22Warfarin 37Digo
xin 42Phenobarbitone 86
Most efficiently eliminated
Least efficiently eliminated
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Clearance with complete extraction
Liver
(10 mg/L)
(0 mg/L)
Assume 2 litres of blood flow through the liver
every minute. 2 litres of blood are completely
cleared of drug every minute. (Clearance 2
litres/min)
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Clearance with incomplete extraction
Liver
(10 mg/L)
(5 mg/L)
Assume 2 litres of blood flow through the liver
every minute. In effect, 1 litre of blood is
completely cleared of drug every minute.
(Clearance 1 litre/min)
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Clearance
The volume of blood that is completely cleared of
drug in a stated period of time. Units should be
ml/hour, litres/day etc.
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Clearance through other organs
Clearance could be via the kidneys. Same
principle applies. If 1 litre of blood flows
through the kidneys every minute and 10 of the
drug is eliminated, clearance is 100 ml/min.
(The removed by the kidneys tends to be lower
than that removed by the liver.)
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Clearance
Why bother with a second measure of drug
elimination when we already have half
life? Clearance can be used in a very simple way
to calculate what dose will be required to
achieve a given blood level of drug. Half life
does not allow such simple calculations.
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Terms with which you should be familiar
Absorption Distribution Elimination Metabolism Cyt
ochrome P450 Excretion
Pharmacokinetics Bioavailability First pass
metabolism Volume of distribution Half
life Clearance