Pharmacokinetics lecture 3 contents
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Pharmacokinetics lecture 3 Contents . Compartments Bioavailability Salt factor. Compartments. T3. Compartment 1 Blood + tissues 1 & 2. Blood. T2. T1. Compartment 2 Tissues 3 & 4. T4. Compartments.

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Pharmacokinetics lecture 3 contents

Pharmacokinetics lecture 3Contents ...

  • Compartments

  • Bioavailability

  • Salt factor


Compartments

Compartments

T3

Compartment 1

Blood + tissues 1 & 2

Blood

T2

T1

Compartment 2

Tissues 3 & 4

T4


Compartments1

Compartments

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


Single compartment

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

T4

Blood

T2

T3


Single compartment1

Single compartment

D

V


Two compartments

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

T4

Blood

T2

T3


Blood flows

Blood flows


Two compartments1

Two compartments

D

V2

V1


Bioavailability f

Bioavailability (F)

  • The fraction of a dose that reaches the systemic circulationin a chemically unaltered form.

  • Fractional availability = F

  • Quote as percentage or decimal e.g. 25% or 0.25

  • Has no units.


Incomplete oral bioavailability

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


Failure of absorption

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


First pass metabolism in the gut wall

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


Oral bioavailability

Oral bioavailability


Pharmacokinetics lecture 3 contents

Blood drainage from G.I.T.

General

circulation

Mouth

Stomach

Small

intestine

Large

intestine

Liver

Rectum

General

circulation


Salt factor s

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


Salt factor s1

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


Sample calculation

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.


Model answer

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


Terms with which you should be familiar

Terms with which you should be familiar ...

Compartment

Bioavailability

First pass metabolism

Salt factor


What you should be able to do

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


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