Drug Metabolism

Question 1

Volume of distribution

Answer 1

Also called Vd; the volume that would contain the total body content (Q) of the drug at an equal concentration of plasma (Cp)

Is essentially a measurement of how well the drug is distributed throughout the body

Question 2

Plasma binding proteins

Answer 2

Albumin is the most abundant plasma binding protein

It has two binding sites and is non-specific, it also does not discriminate between acidic and basic compounds

Binding to the molecule is also reversible

Question 3

Effect of albumin binding on drug activity

Answer 3

When a drug is bound to albumin it cannot have an effect on the tissues

When a drug is bound to a plasma protein it results in reduced elimination, reduced action and potential displacement of drugs already bound

Question 4

Adipose tissue

Answer 4

Most drugs are lipophilic and so are soluble in adipose tissue

This can lead to bioaccumulation within fat tissue

Question 5

Blood flow

Answer 5

For a drug to reach its target, the tissue must have a good blood supply

Well perfused tissues = heart, lungs, liver, brain

Poorly perfused tissues = bones, teeth, tendons, ligaments

Question 6

Membrane barriers

Answer 6

Some organs are protected by specialised membrane barriers, through which normal diffusion cannot occur

These membranes do contain transporters, but they mostly transport substances out of that tissue

Question 7

Metabolism

Answer 7

The body naturally acts to remove chemicals

For a drug to pass out of the body in urine or faeces it must be hydrophilic

Most drugs are hydrophobic

Question 8

Phase I metabolism

Answer 8

A small reactive group is added to the drug to make it more soluble

• oxidation
• reduction
• hydrolysis

These reactions usually involve oxygen and NADPH (compounds that are readily available) and produce water, making them reliable reactions

Question 9

Cytochromes P450

Answer 9

Cytochromes P450 catalyse phase I reactions

They are inducible

CYP1 = polycyclic aromatic hydrocarbons (produce carcinogenic by-products)

CYP2 & CYP3 = many drugs

All CYPs also have endogenous substrates

Question 10

Phase II metabolism

Answer 10

A large, bulky group is added to the molecule to increase hydrophilicity

Commonly added conjugates include glucuronic acid, sulphate, amino acids, glutathione and acetyl groups

Each reaction uses a different, non-specific enzyme that is also inducible

Question 11

Glucuronidation

Answer 11

The primary phase II mechanism

Involves the base unit glucose-1-phosphate

Enzyme = UDP-glucuronyl transferase

A high energy conjugate

Question 12

Sulphation

Answer 12

Involves the addition of two inorganic sulphate molecules

A high energy conjugate

Question 13

Glutathione

Answer 13

Involves the addition of GSH (a tripeptide of glycine, cysteine and glutamate)

A low energy conjugate

Deals with high energy molecules (e.g. halides & epoxides) that can be extremely toxic

Conjugates of glutathione should not occur unless the drug is at a toxic dose

Question 14

Excretion

Answer 14

The main sites of excretion include the kidney, the liver and the GI tract

There are several factors influencing excretion rate:

• Integrity of the kidney
• Molecule size
• Urine flow
• Urine pH