Drug absorption
Learning outcomes
Understand the concepts of :
● Drug dissociation:
- pH-partition hypothesis
- Henderson-Hasselbalch Equation
- Limitations of the pH-partition hypothesis
● Lipid solubility
- Partition coefficient
● Molecular size & hydrogen bonding.
Drug Dissociation and lipid solubility
1. Influencing Factors:
○ Dissociation Constant: Affects the degree of ionization of a drug.
○ Lipid Solubility: Impacts how well a drug can pass through cell
membranes.
○ pH at Absorption Site: Influences the ionization state of the drug and
thus its absorption.
2. pH-Partition Hypothesis (Overton, 1899):
○ Concept: Drug absorption is influenced by its degree of ionization, which
is affected by its dissociation constant and the pH at the absorption site.
○ Mechanism: Drugs pass through cell membranes more effectively if they
are in their non-ionized (lipid-soluble) form.
3. Transcellular Passive Route:
○ Preference: Most drugs are absorbed via this route, where they diffuse
through cell membranes.
4. Framework Usefulness:
○ Simplification: Though oversimplified, the pH-partition hypothesis helps
in understanding the basic principles of drug absorption
, pH-Partition hypothesis
According to the pH-partition hypothesis:
1. Lipid Barrier:
○ The gastrointestinal epithelium acts as a lipid barrier.
○ Drugs absorbed by passive diffusion must be lipid-soluble.
2. Weak Electrolytes:
○ Most drugs are weak electrolytes.
○ Unionized forms (lipid-soluble) pass through the epithelium more easily.
3. pH-Partition Hypothesis:
○ Absorption of weak electrolytes depends on the extent of their unionized
form at the absorption site.
4. Ionization Calculation:
○ Use the Henderson-Hasselbalch equation to determine ionization.
○ For weakly acidic drugs with one ionizable group:
−
[𝐴 ]
𝑙𝑜𝑔 ( [𝐻𝐴]
= 𝑝𝐻 − 𝑝𝐾𝑎
Where:
−
● [𝐴 ]= concentration of ionized form
● [HA] = concentration of unionized form
● pH = pH of the solution
● pKa = acid dissociation constant of the drug
5. Example Drugs: Weakly acidic drugs include aspirin, phenobarbital, and ascorbic
acid (vitamin C).
Learning outcomes
Understand the concepts of :
● Drug dissociation:
- pH-partition hypothesis
- Henderson-Hasselbalch Equation
- Limitations of the pH-partition hypothesis
● Lipid solubility
- Partition coefficient
● Molecular size & hydrogen bonding.
Drug Dissociation and lipid solubility
1. Influencing Factors:
○ Dissociation Constant: Affects the degree of ionization of a drug.
○ Lipid Solubility: Impacts how well a drug can pass through cell
membranes.
○ pH at Absorption Site: Influences the ionization state of the drug and
thus its absorption.
2. pH-Partition Hypothesis (Overton, 1899):
○ Concept: Drug absorption is influenced by its degree of ionization, which
is affected by its dissociation constant and the pH at the absorption site.
○ Mechanism: Drugs pass through cell membranes more effectively if they
are in their non-ionized (lipid-soluble) form.
3. Transcellular Passive Route:
○ Preference: Most drugs are absorbed via this route, where they diffuse
through cell membranes.
4. Framework Usefulness:
○ Simplification: Though oversimplified, the pH-partition hypothesis helps
in understanding the basic principles of drug absorption
, pH-Partition hypothesis
According to the pH-partition hypothesis:
1. Lipid Barrier:
○ The gastrointestinal epithelium acts as a lipid barrier.
○ Drugs absorbed by passive diffusion must be lipid-soluble.
2. Weak Electrolytes:
○ Most drugs are weak electrolytes.
○ Unionized forms (lipid-soluble) pass through the epithelium more easily.
3. pH-Partition Hypothesis:
○ Absorption of weak electrolytes depends on the extent of their unionized
form at the absorption site.
4. Ionization Calculation:
○ Use the Henderson-Hasselbalch equation to determine ionization.
○ For weakly acidic drugs with one ionizable group:
−
[𝐴 ]
𝑙𝑜𝑔 ( [𝐻𝐴]
= 𝑝𝐻 − 𝑝𝐾𝑎
Where:
−
● [𝐴 ]= concentration of ionized form
● [HA] = concentration of unionized form
● pH = pH of the solution
● pKa = acid dissociation constant of the drug
5. Example Drugs: Weakly acidic drugs include aspirin, phenobarbital, and ascorbic
acid (vitamin C).
