Partitioning (pharmacokinetics)

Question 1

Partitioning definition

Answer 1

Partitioning is the distribution (or moving) of a substance between two immiscible phases

Question 2

Partitioning: practical elements

Answer 2

In a laboratory partitioning behaviour would be investigated using a separating funnel

Immiscible liquids added to separating funnel
Drug under investigation added to the mixture
Separating funnel shaken (open tap regularly to release pressure build-up)
Immiscible phases separated and concentration of drug in each liquid determined
Partition coefficient is determined from these values

Question 3

In an ideal solution a partition coefficient (P) can be defined:

Answer 3

Partition coefficient (P) = Co / Cw

Co = conc in organic phase
Cw = conc in aqueous phase

Question 4

What is P?

Answer 4

P is a measure of relative affinity of the solute for an aqueous and a lipid phase at equilibrium – it will be constant
Only applies to dilute solutions, i.e. ideal solutions

Question 5

Log P

Answer 5

The range of the partition coefficients of common drugs is quite large
Often log10 P is used
log P gives an indication of the lipophilicity of a drug

Question 6

Partitioning of weak acids & bases

Answer 6

HA is a weakly acidic drug

HA <> H+ + A-

Let’s assume that the pH of the aq. phase means that no ionisation takes place

If the pH is changed and ionisation occurs in the aqueous phase, then there will be two species present

Question 7

P =

Answer 7

[HA]o / [HA]w

Question 8

Papp =

Answer 8

[HA]o / [HA]w + [A-]w

Degree of ionisation (hence [HA]w) is controlled by pH, so the pH will also alter Papp

Question 9

Partitioning of weak acids & bases

Answer 9

The fraction unionised ( funionised ) in the aqueous phase determines the difference between Papp and P

Question 10

Papp =

Answer 10

P x f unionised

Question 11

What is f unionised?

Answer 11

[HA] / [HA] = [A-]

Question 12

when to use HH equation?

Answer 12

[HA] and [A-] are terms that are found in the Henderson-Hasselbalch equation

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So, it’s possible to combine this first equation with the Henderson-Hasselbalch equations for weak acids and weak bases to relate P, Papp, pKa and pH

Question 13

Partitioning of weak acids:

Answer 13

Log [ P/Papp - 1] = pH - pKa

Question 14

Partitioning of weak bases:

Answer 14

Log [ P/ Papp - 1] = pKa - pH

Question 15

Pharmaceutical relevance

Answer 15

Drugs typically need to pass several lipophilic barriers, e.g. intestinal membrane, cell membranes, blood-brain barrier etc. before they can exert an affect

Aqueous solubility also important as the drug molecule is typically required to be in solution for absorption to occur

Balanced hydrophilic-lipophilic properties are required

Log P is a useful measure of this balance

Question 16

In distribution flask…

Answer 16

Organic phase equivalent to lipophilic regions in the body

Aqueous phase equivalent to aqueous regions in the body

Question 17

o/w emulsion

Answer 17

Preservatives are often used in oral liquid formulations – this can present challenges with emulsions / creams

Concentration of preservative in the aqueous phase may be lower that we had calculated

Question 18

Drugs with high log P values…

Answer 18

readily partition into rubber or plastic substances, e.g. containers, stoppers, septa, infusion bags/lines

Question 19

Glyceryl trinitrate (GTN) a volatile drug with a relatively high log P of 2.154 will partition from tablets into plastic packages (up to 50%)

Problem for what type of rugs specifically?

Answer 19

This can be a major problem for storage of lipophilic drugs

Question 20

MAC

Answer 20

minimum alveolar concentration (the lower this is the more potent the anaesthetic is)

axis vertical on graph

Question 21

What are the 2 axis on the graph

Answer 21

1) MAC
2) Oil/gas partition coefficient