D2 Partition coefficient, logP and bioavailability Flashcards
what is partitioning?
- the distribution (or moving) of a substance between 2 immiscible phases
- this is a dynamic equilibrium (the molecules are moving between the 2 phases)
how is the partition coefficient (P) calculated?
- in an ideal solution, a partition can be defined as detailed in the image
describe the partition coefficient (P)
- 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
how is P calculated? give the method, not the calculation
- 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)
what P values does octanol tend to produce?
those which correlate better with in vivo biological data
why is P often expressed as logP instead?
- the range of the partition coefficients of common drugs is quite large so using log makes the expression of P more simple
what does logP give an indication of?
the lipophilicity of a drug
what do large and small values of logP indicate?
large logP = oil-loving (lipophilic)
small logP = water-loving (hydrophilic)
what is amiodarone? describe it in terms of its lipophilicity and what can occur in overdose
- 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
what are drugs often? (in terms of molecule classification)
weak electrolytes (ionise in at least one phase - usually aqueous phase)
how does the partitioning of weak electrolytes make complications?
- complicates the partitioning process
- fully ionised salt is more soluble in the aqueous phase then the unionised salt
how do we define the ‘true’ partition coefficient?
how can partition coefficient by defined with more than 1 molecular species eg. with drug ionisation?
describe the calculation of the partition coefficient (P) for a weak acid assuming the pH of the aqueous phase means no ionisation takes place
- 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
describe the partitioning of weak electrolytes
- the fraction unionised in the aqueous phase determines the difference between Papp and P
what is the fraction unionised as a formula?
where are [HA] and [A-] found? what does this make possible?
- 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
what is the equation for weak acids linking P, Papp, pH and pKa?
what is the equation for weak bases linking P, Papp, pH and pKa?
why is the pH partition hypothesis relevant to pharmacy?
only unionised drugs can pass through cell membranes
how are partitioning and drug absorption related?
- 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
what do drugs with high logP values readily partition into?
- rubber or plastic containers
- many formulations are affected
describe and explain the partitioning of GTN and its resultant packaging
- 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
what problems can occur with IV drugs with a high logP?
administration of high logP drugs as an IV infusion is an issue due to going through plastic piping
describe partitioning and preservative availability
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
often, where is the site of action of drugs?
in (or on the other side of) lipid compartments
how are drugs delivered to their lipid compartments that are their sites of action?
via an aqueous compartment (blood)
what sometimes exist between logP and biological effect?
- correlations
- many simple organic compounds exert a depressant (narcotic) action on organisms (no chemical specificity)
what is a QSAR?
quantitative structure-activity relationship
what are equations derived from and how does this relate to QSARs?
- 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
lots of assumptions are made when regarding drug absorption. what complexities actually exist in reality surrounding drug absorption?
- 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
in reality, drug absorption is more complex than assumed. what does this mean for ionised drugs? give an example
- 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%)
describe the concept of ion pairing
- ionised drugs may combine with an oppositely charged ion
- the ion=pair behave as a neutral species and permeate the gastric mucosa
why may active transport mechanisms exist in the body?
molecules may be so vital to the body that they are required
state 4 examples of substances that active transport mechanisms exist for
ions (sodium, chloride etc)
glucose
amino acids
vitamins
what does active transport allow for?
- molecules can be absorbed even if they are ionised or highly hydrophilic
how can drugs be absorbed by active transport?
- 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
