D2 Partition coefficient, logP and bioavailability

Question 1

what is partitioning?

Answer 1

• the distribution (or moving) of a substance between 2 immiscible phases
• this is a dynamic equilibrium (the molecules are moving between the 2 phases)

Question 2

how is the partition coefficient (P) calculated?

Answer 2

• in an ideal solution, a partition can be defined as detailed in the image

Question 3

describe the partition coefficient (P)

Answer 3

• P may also be referred to as a ‘distribution coefficient’
• 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

Question 4

how is P calculated? give the method, not the calculation

Answer 4

• drug added to separating funnel containing 2 immiscible liquids
• the flask is (mechanically) shaken for up to 1 hour and then left to separate out
• concentrations in each phase are determined so P can easily be calculated
• ‘partition coefficient’ may refer to the partitioning between any 2 immiscible phases (most common are octanol and water)

Question 5

what P values does octanol tend to produce?

Answer 5

those which correlate better with in vivo biological data

Question 6

why is P often expressed as logP instead?

Answer 6

• the range of the partition coefficients of common drugs is quite large so using log makes the expression of P more simple

Question 7

what does logP give an indication of?

Answer 7

the lipophilicity of a drug

Question 8

what do large and small values of logP indicate?

Answer 8

large logP = oil-loving (lipophilic)
small logP = water-loving (hydrophilic)

Question 9

what is amiodarone? describe it in terms of its lipophilicity and what can occur in overdose

Answer 9

• hypertension drug
• if given in too high quantity, patient can go blue
• segregates to the lipophilic cell bilayers and gets to a very high concentration

Question 10

what are drugs often? (in terms of molecule classification)

Answer 10

weak electrolytes (ionise in at least one phase - usually aqueous phase)

Question 11

how does the partitioning of weak electrolytes make complications?

Answer 11

• complicates the partitioning process
• fully ionised salt is more soluble in the aqueous phase then the unionised salt

Question 12

how do we define the ‘true’ partition coefficient?

Answer 12

Question 13

how can partition coefficient by defined with more than 1 molecular species eg. with drug ionisation?

Answer 13

Question 14

describe the calculation of the partition coefficient (P) for a weak acid assuming the pH of the aqueous phase means no ionisation takes place

Answer 14

• if the pH is changed and ionisation occurs in the aqueous phase, you might see something like this…(image)
• in pink, degree of ionisation (hence [HA]w) is controlled by pH, so the pH will also alter Papp

Question 15

describe the partitioning of weak electrolytes

Answer 15

• the fraction unionised in the aqueous phase determines the difference between Papp and P

Question 16

what is the fraction unionised as a formula?

Answer 16

Question 17

where are [HA] and [A-] found? what does this make possible?

Answer 17

• both found in the Henderson-Hasselbalch equation
• therefore it is possible to combine this first equation with the HH equations for weak acids and weak bases to relate P, Papp, pKa and pH

Question 18

what is the equation for weak acids linking P, Papp, pH and pKa?

Answer 18

Question 19

what is the equation for weak bases linking P, Papp, pH and pKa?

Answer 19

Question 20

why is the pH partition hypothesis relevant to pharmacy?

Answer 20

only unionised drugs can pass through cell membranes

Question 21

how are partitioning and drug absorption related?

Answer 21

• the site of action of a drug is typically behind several lipophilic barriers (intestinal membrane, cell membranes, BBB etc.)
• aqueous solubility is also important as the drug molecule is typically required to be in solution for absorption
• therefore, balanced hydrophilic-lipophilic properties are required
• logP can be used as a measure of this balance

Question 22

what do drugs with high logP values readily partition into?

Answer 22

• rubber or plastic containers
• many formulations are affected

Question 23

describe and explain the partitioning of GTN and its resultant packaging

Answer 23

• glyceryl trinitrate (GTN) is a volatile drug with a relatively high logP of 2.154
• it will partition from tablets into plastic packages (up to 50%)
• therefore, GTN tablets are supplied in glass bottles, NOT plastic blister packs

Question 24

what problems can occur with IV drugs with a high logP?

Answer 24

administration of high logP drugs as an IV infusion is an issue due to going through plastic piping

Question 25

describe partitioning and preservative availability

Answer 25

if the preservative is a weak acid / base, a solution to the problem could be to adjust the pH to favour ionisation (I.e. more likely to partition into water) but many preservatives are only active in the unionised form

Question 26

often, where is the site of action of drugs?

Answer 26

in (or on the other side of) lipid compartments

Question 27

how are drugs delivered to their lipid compartments that are their sites of action?

Answer 27

via an aqueous compartment (blood)

Question 28

what sometimes exist between logP and biological effect?

Answer 28

- correlations - many simple organic compounds exert a depressant (narcotic) action on organisms (no chemical specificity)

Question 29

what is a QSAR?

Answer 29

quantitative structure-activity relationship

Question 30

what are equations derived from and how does this relate to QSARs?

Answer 30

- equations derived from experimental data which relate the structure of a drug to its pharmacological activity (or absorption) - QSAR extrapolated to other drugs to predict activity or absorption without doing the experiment

Question 31

lots of assumptions are made when regarding drug absorption. what complexities actually exist in reality surrounding drug absorption?

Answer 31

- the small intestines are designed for absorption - surface area of up to 200 m squared as a result of microvilli - long residence time - excellent blood flow

Question 32

in reality, drug absorption is more complex than assumed. what does this mean for ionised drugs? give an example

Answer 32

- this means that even drugs which are ionised can be absorbed to a considerable extent in the small intestine - this is due to the large surface area, long residence time and excellent blood flow - eg. oral anti diabetic drug metformin is almost entirely ionised at the pH of the stomach but it is mainly absorbed in the small intestine (bioavailability = 50%)

Question 33

describe the concept of ion pairing

Answer 33

- ionised drugs may combine with an oppositely charged ion - the ion=pair behave as a neutral species and permeate the gastric mucosa

Question 34

why may active transport mechanisms exist in the body?

Answer 34

molecules may be so vital to the body that they are required

Question 35

state 4 examples of substances that active transport mechanisms exist for

Answer 35

ions (sodium, chloride etc) glucose amino acids vitamins

Question 36

what does active transport allow for?

Answer 36

- molecules can be absorbed even if they are ionised or highly hydrophilic

Question 37

how can drugs be absorbed by active transport?

Answer 37

- some drug molecules resemble vital compounds and may be actively absorbed - the anticancer drug melphalan is similar instructor to phenylalanine so is actively absorbed in the GIT