pH-partition theory

Question 1

pH-partition theory

Answer 1

• The greater the proportion ionised then the lower the overall absorption will be
• Absorption of weak acids and bases is determined by the degree of ionisation

Question 2

GI and drug absorbtion

Answer 2

• Epithelium
  acts as a lipoidal barrier to
  drug absorption
• Somach pH can be as low as 1.5 pH then drug goes to a higher pH
• Weak base more likely to be absorbed in the small intestine when pH is greater than 5.5

Question 3

pH-partition theory limitations

Small intestines are better designed for absorption

Answer 3

• Surface area of the small intestines is up to 200 m2 as a result of microvilli
  − Drugs have a longer residence time in the small intestines than the
  stomach
  − Small intestines have an excellent blood supply

Question 4

Metformin

Answer 4

• Almost entirely ionised at the pH of the small intestines
• Mainly absorbed in the small intestines

Question 5

pH-partition theory limitations

pH of the bulk gastro-intestinal fluid

Answer 5

• Difference in surface with epithelium with the local pH
• 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

pH-partition theory limitations

Ion paired

Answer 6

• Ion-pairing is when oppositely charged ions are held together without the formation of a covalent bond
• Ion-pair behave as a neutral species and may be better able to permeate the gastric mucosa

Question 7

pH-partition theory limitations

Requirement of ATP

Answer 7

• Mechanisms exist for some molecules/ions
  that are particularly vital to the body
• Allows substances such as Ions (Na+, Cl–), Glucose, Vitamins and Amino acids to exit
• 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

pH-partition theory limitations

Melphalan AND phenylalanine

Answer 8

• Are an anticancer drug which has a similar molecular structure absorbed actively in the GI

Question 9

pH, partitioning and breastfeeding

Answer 9

• Milk readily available, free, sterile, temperature, nutritional requirement
• pKa of drug (milk has a mean pH of 7.2), Degree of plasma protein binding and Log P of drug

Question 10

Milk:Plasma ratio

Answer 10

• Low, but also need to consider
  maternal dose, amount of milk drunk by the baby, toxicity

Question 11

Partitioning and drug excretion

Answer 11

• Kidney unionised drug may partition from the blood to lipid membrane to urine
• If urine pH favours the ionised form of the drug excreted in the urine
• Unionised form is favoured reabsorbed in circulation loop of henle
• Renter circulatory system free to exert theraputic effect

Question 12

Renal excreation of partioning drugs

Answer 12

• Altering the pH of the urine with salt solutions, e.g. sodium citrate which is urine alkaliniser

Question 13

What does acidic urine mean?

Answer 13

• Weak basic drugs are more likely to be ionised
  − Decrease in re-absorption & increase in excretion

Question 14

What does alkaline urine mean?

Answer 14

• Weak basic drugs are more likely to be unionised
  − Therefore increase in re-absorption and decrease in excretion