CPTP 2.2

Question 1

Describe first pass metabolism and its importance

Answer 1

First pass metabolism = metabolism in the gut/liver

High first pass metabolism leads to low bioavailability

Question 2

Define bioavailability

Answer 2

The proportion of a drug that passes into the systemic circulation after administration

Question 3

How is bioavailability influenced by drug absorption?

Answer 3

Solubility of the drug
e.g. hydrophilic drugs are poorly absorbed, so they have low bioavailability

Chemical instability in the GI tract leads to low bioavailability

Drug formulation

Question 4

First pass metabolism Question.

Only 30-40% of an oral dose of morphine reaches the systemic circulation. What will be the oral dose of morphine compared to its IV dose?

Answer 4

three times the IV dose

If a drug is administered intravenously we say the drug has 100% bioavailability

Question 5

Reactions involved in phase I metabolism

Answer 5

Oxidation (most common and CYP enzyme mediated)

Reduction (CYP-mediated)

Hydrolysis

Question 6

Describe phase I metabolism

Answer 6

Usually form more chemically reactive products

Parent drug –> Derivative drug

Products are used in phase II metabolism and subsequent excretion

Question 7

Describe phase II metabolism

Answer 7

• Conjugation reactions
• Decreases lipid solubility and almost always results in pharmacologically inactive metabolite
• Conjugate excreted in urine or bile
• Commonest conjugation reaction is glucuronidation

Question 8

Describe glucuronidation

Answer 8

• Mediated by UDP-glucuronyl transferases (UDPGTs)

- steroids, vitamins, bile acids and bilirubin undergo this reaction

Question 9

Three different routes of excretion

Answer 9

1. Renal excretion (in urine)
   glucoronide conjugates of MW <400
2. Biliary excretion (in faeces)
   glucoronide conjugates of MW >400, MW 500 being optimal
3. Lungs for excreting volatile compounds

Question 10

Glucuronide conjugates excreted in bile may undergo enterohepatic circulation. Explain enterohepatic circulation.

Answer 10

1. Drug is metabolised to conjugate in liver
2. Conjugate is excreted in the bile from gall bladder into the gut
3. Conjugate undergoes bacterial hydrolysis in gut back into drug and free glucuronide
4. Drug is reabsorbed into hepatic portal vein and transported to liver. Here, parent drug may be reabsorbed into blood resulting in prolonged duration of action, increasing half life.

Question 11

Describe the first step of renal excretion - glomerular filtration.

Answer 11

• 20% of renal blood flow
• Plasma bound proteins are almost completely held back
• Lipid solubility and pH do not affect GF

Question 12

Describe the second step of renal excretion - active tubular secretion

Answer 12

• 80% of renal blood flow
• Occurs in the proximal tubule
• Transported along with organic cations/anions
• Plasma bound proteins is not a barrier to carrier mediated transport
• Not affected by pH

Question 13

Describe the final step of renal excretion - tubular reabsorption

Answer 13

• Affected by lipid solubility and pH
• Highly water soluble drugs diffuse back into the bloodstream –> lowly excreted
• Changes in urine pH can alter drug ionisation and therefore excretion