pH-partition theory (pharmacokinetics)

Question 1

pH-partition theory states

Answer 1

the greater the proportion ionised then the lower the overall absorption will be

Question 2

pH-partition theory states that the absorption of weak acids and bases is determined by the degree of ionisation

which equation?

Answer 2

HH

Question 3

What are the limitations of the pH partition theory?

Answer 3

• small intestines better designed for absorption than stomach
• surface area SI up to 200m^2 = microvilli
• drugs - longer residence time in small intestines than stomach
• SI excellent blood supply
• even drugs which are ionised can be absorbed to a considerable extent in small intestines
• metformin (weak base) entirely ionised at pH of SI, mainly absorbed in SI
• pH of the bulk gastro-intestinal fluid may differ from that at the surface or within the epithelium, i.e. the local pH
• Degree of ionisation is not the only determinant of absorption from the GI tract

Question 4

So that the equilibrium remains approximately __%/__% one of the ionised drug molecules will need to gain a proton

Answer 4

10 % / 90%

Question 5

Factors that limit the pH partition theory:

Answer 5

Molecular weight
Lipid solubility (log P often used as a proxy)
Water solubility
Binding to Ca2+, Mg2+, Al3+ present in milk, antacids etc.
Ion-pairing
Presence of active transport mechanisms

Question 6

Ion-pairing is when oppositely charged ions are held together without the formation of a covalent bond

Answer 6

The ion-pair behave as a neutral species and may be better able to permeate the gastric mucosa

Question 7

Active transport - pH-partition theory limitations

Answer 7

exist for some molecules/ions that are particularly vital to the body

Mechanisms exist for substances such as:
Ions (Na+, Cl–)
Glucose
Vitamins
Amino acids

These transport mechanisms require energy, i.e. it is not just passive diffusion

This 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 by the same mechanisms

Question 8

anti-cancer drug

Answer 8

Melphalan is an anti-cancer drug indicated for several conditions including multiple myeloma
It is similar in molecular structure to phenylalanine and is actively absorbed in the GI tract

Question 9

pH, partitioning and breastfeeding:

Answer 9

advantages of breastfeeding:
- free
-sterile
- nutritional requirement
- temperature
- milk readily available

Question 10

Three parameters determine the degree of drug distribution into breast milk:

Answer 10

1) pKa of drug (milk has a mean pH of 7.2)

2) Degree of plasma protein binding

3) Log P of drug (milk fat content varies from 4 – 9%)

M/P ratios (milk : plasma drug concentration ratios) are published – ideally will be low, but also need to consider maternal dose, amount of milk drunk by the baby, toxicity
BNF offers advice on prescribing to breast-feeding mothers

Question 11

What determines if drugs gets excreted or not?

Answer 11

pKa of drug and pH value of urine

Question 12

pH, partitioning and drug excretion

Answer 12

In the kidney unionised drug may partition from the blood (pH 7.4) > lipid membrane > urine

If urine pH favours the ionised (water-soluble) form of the drug > excreted in the urine

If unionised form is favoured, the molecule may be reabsorbed back into the circulation by passing back through the lipid membrane in Loop of Henle

Drug re-enters the circulatory system, free to exert its therapeutic action again

Question 13

acidic and alkaline urine

Answer 13

Renal excretion of drugs can be controlled by altering the pH of the urine with salt solutions, e.g. sodium citrate which is urine alkaliniser

Acidic urine:
Weak basic drugs are more likely to be ionised
Decrease in re-absorption & increase in excretion

Alkaline urine:
Weak basic drugs are more likely to be unionised
Therefore increase in re-absorption and decrease in excretion