D2. Partition coefficient, LogP and Bioavailability Flashcards
what is partitioning?
Partitioning is the distribution (or moving) of a substance between two immiscible phases
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partition coefficient (P) equation?
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How to calculate partition coefficient (P)?
-Drug added to a separating funnel containing two immiscible liquids
-The flask is (mechanically) shaken for up to 1 hour and then left so that the two phases separate out
-Concentration in the aqueous phase (CW) is determined by a suitable method, e.g. spectroscopy or titration
-Concentration in the organic phase (CO)would be determined by subtraction
-P can then easily be calculated
Describe Log P
-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
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Describe partitioning of weak electrolytes
-P is constant only if a single molecular species is involved (Nernst, 1891)
-Drugs are often weak electrolytes ionise in at least one phase (usually aqueous phase)
-Complicates the partitioning process fully ionised salt is more soluble in the aqueous phase than the unionised salt
-Since P is only constant for a single molecular species, e.g. the unionised drug, then assay data would need to be corrected to allow for ionisation
-Often, an apparent partition coefficient (Papp), where ionisation and its consequences are ignored, is used instead
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What is the funionised ?
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The pH partition hypothesis?
Only nonionized drugs can pass through cell membranes.
Describe partitioning and drug absorption
-The site of action of a drug is typically behind several lipophilic barriers, e.g. intestinal membrane, cell membranes, blood-brain barrier etc.
-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 can be used as a measure of this balance
Describe partitioning and polymers
-Drugs with high log P values readily partition into rubber or plastic containers
-Many formulations affected (aqueous solutions or even tablets)
-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%)
-This can be a major problem for storage of lipophilic drugs
-Also an issue with the administration of high log P drugs as an intravenous infusion 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
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Describe partitioning and pharmacology
-Site of action of many drugs is often in (or the other side of) lipid compartments
-The drug is delivered to the site of action in an aqueous compartment (blood)
-The pH partition hypothesis:
Only nonionized drugs can pass through cell membranes.
-Correlations sometimes exist between log P and biological effect
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Describe partitioning and QSARs
-QSAR = quantitative structure–activity relationship
-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
-Terms commonly used in QSAR:
Log P and MW
Describe pH-partition theory limitations
-In reality the situation regarding drug absorption is more complex:
-The small intestines are designed for absorption
-Surface area of up to 200 m2 as a result of microvilli
-Long residence time
-Excellent blood flow
-This means that even drugs which are ionised can be absorbed to a considerable extent in the small intestines
-The oral antidiabetic drug metformin is almost entirely ionised at the pH of the small intestines, yet it is mainly absorbed in the small intestines (bioavailability: 50%)
EXAMPLE ON ONE NOTE
Describe ion pairing
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Active transport mechanisms exist for substances such as:
Ions (Na+, Cl–)
Glucose
Vitamins
Amino acids
-Active transport means that molecules may be absorbed even if they are ionised or highly hydrophilic
-Some drug molecules resemble vital compounds and may be actively absorbed
