Drug Absorption

Question 1

Define ADME and describe its importance

Answer 1

A – absorption
Process by which unchanged drug enters the circulation
D – distribution
Dispersion of a drug among fluids and tissues of the body
M – metabolism
Transformation of a drug into daughter compound(s)
E – excretion
Removal of drugs/metabolites from the body

Question 2

Describe the key factors governing drug absorption

Answer 2

• Medicines need to be absorbed unless given directly into the circulation
• Different routes of administration present different barriers to absorption
• Different routes of administration result in different bioavailability and onset

-Choice of delivery route is a compromise
–Speed of onset
–Convenience: oral or i.v.?
–Bioavailability: proportion of administered drug reaching the systemic circulation – 100% for drugs given i.v.
–Side effects / specificity of action

Absorption requires drugs to cross biological barriers (layers of cells with semi-permeable, lipophilic membranes)
Most absorption occurs through cells, some occurs between cells

Absorption can occur by:
–active transport through cells (very few medicines)
–facilitated diffusion through cells (few medicines)
–passive diffusion (most medicines)

Question 3

Define the Henderson-Hasselbach equation

Answer 3

-predict extent of ionisation
For acids: pH = pKa - log [non-ionised] / [ionised]

For bases: pH = pKa + log [non-ionised] / [ionised]

pH = pKa when drug is 50% ionized

Acidic drugs: the more unionised the drug will be as pH becomes more acidic
Basic drugs: the more unionised the drug will be as pH becomes more alkali

Question 4

Describe the process of ion trapping

Answer 4

• Acidic drugs are absorbed efficiently from the stomach
  Basic drugs are absorbed less efficiently
  Note that the same principles apply to the renal excretion of drugs (alkaline urine traps and enhances excretion of acidic drugs)

Question 5

Define the Lipinski Rules

Answer 5

An orally-active drug likely has no more than one violation of the following:

Molecular weight < 500 da
•No more than 5 H-bond donors
•No more than 10 H-bond acceptors
•Log P < 5 (partition coefficient)

Question 6

Key factors in determining the speed of onset of a drug’s effects, their duration of action and the potential for problems in special cases;

Answer 6

• Essential for the safe and intelligent use of medicines by all doctors – essential for treatment
• Designing dosing regimens
• Monitoring treatment compliance
• Medicine licensing requirement
• Substance of abuse monitoring
• Essential for the safe and intelligent use of medicines by all doctors – essential for treatment
• Designing dosing regimens
• Monitoring treatment compliance
• Medicine licensing requirement
• Substance of abuse monitoring

Question 7

Summary of drug absorption

Answer 7

Absorption essential for drugs to obtain access to site of action
Most drugs are absorbed by passive diffusion - Fick’s Law factors influence this (surface area, ionisation, lipid solubility, concentration)
Unless transported, transcellular drug absorption requires drug to be uncharged
Absorption at complex (thick) barriers slower than at simple barriers
Absorption is modified by ion trapping where a change in ionisation accompanies absorption
The Lipinski Rules define the optimum approaches for ADME