Pharmacokinetics lecture 3 Contents ...

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Pharmacokinetics lecture 3Contents ...

• Compartments
• Bioavailability
• Salt factor

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Compartments
T3
Compartment 1 Blood tissues 1 2
Blood
T1
T2
Compartment 2 Tissues 3 4
T4
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Compartments

• The sum of all those tissues into which a drug
  distributes at approximately the same rate.

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Single compartment
All tissues penetrated rapidly or not at
all. Combine blood and all penetrated tissues
(T1 T2) as a single compartment. Drug assumed
to spread instantly throughout all of this
space.
T1
Blood
T2
T4
T3
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Single compartment
D
V
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Two compartments
Drug penetrates some tissues rapidly and others
slowly. Combine blood and rapid tissues (T1 T2)
as first compartment. Drug spreads instantly
through this compart-ment. Combine slow tissues
(T3 T4) as second compartment.
T1
Blood
T4
T2
T3
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Blood flows
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Two compartments
D
V2
V1
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Bioavailability (F)

• The fraction of a dose that reaches the systemic
  circulation in a chemically unaltered form.
• Fractional availability F
• Quote as percentage or decimal e.g. 25 or
  0.25
• Has no units.

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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 Pgp efflux
Liver
1. Failure of disintegration or dissolution
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Failure of absorption

• May be due to
• Binding to other molecules in the gut contents
• Too polar to undergo passive diffusion
• Efflux due to P-glycoproteins

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First pass metabolism in the gut wall
Intestinal epithelium is rich in drug
metabolising enzymes. Main Cyt P450 is CYP3A4
Cytochrome P450 activity in intestinal epithelium
relative to liver ()
Duodenum Ileum
Colon
50 30 10
2
Jejunum
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Oral bioavailability
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Blood drainage from G.I.T.
General circulation
Mouth
Stomach
Small intestine
Large intestine
Liver
Rectum
General circulation
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Salt factor (S)
The drug administered may not be chemically
identical to the drug measured in blood. e.g.
Phyllocontin tablets contain 225mg of
aminophylline. But, target plasma conc. normally
quoted as a theophylline conc. Aminophylline
contains approx. 80 theophylline by weight.
S 0.80
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Salt factor (S)
Predict initial plasma concentration of
theophylline when 500 mg aminophylline injected
i.v. into 70 kg adult. (V 0.48 L/kg) V
0.48 L/kg x 70 kg 33.6 L C D x S
500 mg x 0.80 V
33.6 L 11.9 mg/L
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Sample calculation
A drug is administered as a complex containing
75 (by weight) of the parent drug. The volume
of distribution of the drug is 1.8 L/kg. What
dose of the complex would need to be administered
(i.v) to a 90kg patient in order to achieve an
initial plasma concentration of 15µg/L? The dose
should be expressed in units of mg.
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Model answer
V 1.8L/Kg x 90Kg 162 Litres V D/C0 D
V x C0 S 162L x 15µg/L
0.75 3,240 µg 3.24 mg
Take account of use of a salt
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Terms with which you should be familiar ...
Compartment Bioavailability First pass
metabolism Salt factor
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What you should beable to do

• Describe 1 and 2 compartment systems
• Relate differences in blood flow in various
  tissues to the behaviour of a two compartment
  system
• Define Bioavailability
• List factors that may limit oral bioavailability
• Describe how buccal or rectal administration may
  increase bioavailability
• Incorporate a salt factor into pharmacokinetic
  calculations