Metabolism and excretion

Question 1

Factors affecting metabolism

Answer 1

• The structure of a drug influences its physicochemical properties
• The more complex the structure, the more the potential sites for metabolism
• Blocking/altering sites of metabolism can improve availability of the drug

Question 2

The two phases of drug metabolism

Answer 2

1. Phase I - oxidative transformations: production of new polar groups are introduced or exposed by oxidation, reduction or hydrolysis
2. Phase II - conjugation: original drug or its metabolite made more polar by conjugation reactions

Question 3

Phase I of metabolism

Answer 3

• Oxidation: aliphatic or aromic hydroxylation (OH added to the molecule)
• Reduction: nitro reduction to hydroxylamine/amine (NO2 to NH2)
• Hydrolysis: ester or amide to acid or alcohol or amine

Question 4

Phase II of metabolism

Answer 4

Three things can be added:
1. Sugar - very polar and water soluble, will make the compound more hydrophillic
2. Sulphate
3. Glutathione - acid groups on both sides to make it more soluble
* Glucuronidation: can be done to carboxylic acid, alcohol, phenol or an amine
* Sulphation: can be done to an alcohol, phenol or amine
* Glutathion conjugation: can be done to halogenated-compunds and epoxides

Question 4

Phase II of metabolism

Answer 4

Three things can be added:
1. Sugar - very polar and water soluble, will make the compound more hydrophillic
2. Sulphate
3. Glutathione - acid groups on both sides to make it more soluble
* Glucuronidation: can be done to carboxylic acid, alcohol, phenol or an amine
* Sulphation: can be done to an alcohol, phenol or amine
* Glutathion conjugation: can be done to halogenated-compunds and epoxides

Question 5

Prodrugs

Answer 5

• An inactive compound converted to an active compound in the body
• Used to improve ADME properties
  How prodrugs are used:
  1. Improve membrane permeability by reducing polarity (e.g. carboxylic acid to an ester)
  2. Improve prolong drug activity by releasing the active compound slowly
  3. Mask toxicity/side effects
  4. Alter physicochemcial properties
  5. Targeting drugs to specific sites
  6. Tap into metabolic pathways

Question 6

Renal excretion of drugs

Answer 6

1. All unbound drug in plasma is filtered in the glomerulus
2. Some compounds are actively secreted into urine along the proximal tubule
3. Unionised drugs can undergo passive reabsorption from urine into blood along the length of the nephron
4. Drug that is bound to plasma proteins is not filtered
5. Compounds of high solubility are readily excreted in urine
6. Polar compounds cannot diffuse back into circulation and so will be easily excreted