Drug metabolism and Pharmacokinetics

Question 1

Define drug metabolism

Answer 1

• Drug metabolism is biochemical modification of pharmaceutical substances by living organisms usually through specialized enzymatic activity. Metabolism is divided into two phases (I and II)
• Is an essential pharmacokinetic process, which limits the life of a substance in the body, by rendering lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted.

Question 2

What is the purpose of drug metabolism?

Answer 2

• To increase water solubility and so aid excretion

* Or to deactivate compounds (may involve a number of steps)

Question 3

Describe some possible effects of metabolism,

Answer 3

• Loss of pharmacological activity.
• Decrease in activity, with metabolites that show some activity.
• Increase in activity, more active metabolites.
• Activation of a prodrug.
• Production of toxic metabolites.
• Direct toxicity
• Carcinogenesis.
• Teratogenesis

Question 4

Describe some phase I reactions and what their role is

Answer 4

Oxidation
Reduction
Hydrolysis

Increases the polarity of a compound by introducing or revealing a polar group to provide an active site for phase II metabolism,

Question 5

Describe the action of CYP3A4

Answer 5

Major metaboliser of a wide range of drugs, including diazepam and methadone

Question 6

Describe the action of CYP2D6 and any implications

Answer 6

Metabolises some antidepressants, antipsychotics and the conversion of prodrug codeine to morphine.

Reduced or absent expression in 5-10% of population, making them immune to analgesic effect of codeine

Induced by smoking - problem in psychiatric patients

Question 7

Describe the action of CYP1A2 and any implications

Answer 7

Important in the metabolism of theophylline (COPD drug), which is induced by smoking, meaning smokers require higher doses

Question 8

What types of reactions occur in phase II metabolism, and what effect do they have on the drugs?

Answer 8

Conjugation reactions to increase their water solubility and therefore aid in their secretion

Question 9

What groups can be added in conjugation reactions?

Answer 9

Glucuronic acid
Glutathione
Sulphate
Acetate

Question 10

What effect does enzyme induction have on drug metabolism?

Answer 10

Causes increased metabolism, which results in the decreased effect of the drug, meaning higher doses may be needed.

Question 11

What effect does enzyme inhibitors have on drug metabolism?

Answer 11

Causes decreased metabolism, meaning drugs accumulate in the body and may cause a variety of toxic side effects

Question 12

Describe some factors which affect drug metabolism

Answer 12

Other drugs- DDIs, induction and inhibition
Age - infants, young adults and elderly
Sex - females more likely to have toxicity issues
Ethnicity - CYP2D6 polymorphisms
Certain food stuffs eg. grapefruit
Genetics - fast and slow acetylators
Hepatic blood flow and disease
Pregnancy - induction in 2nd and 3rd trimester