5. Pharmacokinetics: Drug metabolism & excretion

Question 1

Metabolism

Answer 1

• Major mechanism for drug elimination
• Liver is a major site
• Initial compound → metabolites

Question 2

Metabolites

Answer 2

• More polar than the parent compound
• Usually terminates pharmacological action & ↑ removal of drug

Question 3

↑ Polarity

Answer 3

• May lead to a more rapid rate of clearance because of possible secretion by acid or base carriers in kidney
• ↓ Tubular reabsorption

Question 4

Potency of metabolites

Answer 4

May have higher or lower potencies

• Qualitatively different pharmacological actions
• Toxic, active from inactive pro-drugs

Question 5

Xenobiotics

Answer 5

Compounds that are ingested and cannot be used as food

• Harmful if they accumulate in cells
• Detoxified by xenobiotic-metabolising enzymes

Question 6

Biotransformation

Answer 6

The mechanism for drug elimination

Question 7

Give examples of xenobiotics

Answer 7

• Synthetic drugs
• Natural poisons
• Antibiotics

Question 8

Give examples of xenobiotic-metabolising enzymes

Answer 8

• Cytochrome P450 oxidase
• UDP-glucuronosyl transferase
• Glutathione S-transferase

Question 9

Give phase I of xenobiotic-metabolising enzyme action

Answer 9

• Non-synthetic reactions, enzyme catalysed
• Oxidation/reduction
• Hydrolysis
• Introduction of a functional group (e.g OH)
• E.g Cytochrome P450 oxidases

Question 10

The majority of small-molecule drug metabolism is carried out in the liver by…

Answer 10

Redox enzyme - Cytochrome P450

Question 11

Give phase II of xenobiotic-metabolising enzyme action

Answer 11

• Synthetic reaction, conjugation reaction
• Combine drug or metabolite with endogenous substance
• Requires a functional group
• Requires energy indirectly for the synthesis of “active carriers”
• E.g Glucuronyl transferase, sulfotransferase, glutathione transferase

Question 12

Cytochrome P450: Induction

Answer 12

Pharmacologically IMP as major source of drug interactions

• Drug may induce its own metabolism & that of other drugs

Question 13

Cytochrome P450: Inhibition

Answer 13

Competitive or non-competitive inhibition of CYP450 enzyme activity

• Results in ↓ metabolism of other drugs or endogenous substates

Question 14

Glucuronyl transferase

Answer 14

Set of enzymes with unique but overlapping specificities that are involved in phase II reactions

• Catalyses conjugation of glucuronic acid to a variety of active centres
• Located in ER

Question 15

Excretion

Answer 15

Removal from body

• Usually through kidneys or in faeces
• Can also be removed by saliva, sweat, milk, lungs
• Drugs may also be reabsorbed from intestines

Question 16

Net renal excretion

Answer 16

Result of 3 separate processes:

• Filtration
• Secretion
• Reabsorption

Question 17

Filtration

Answer 17

Most drugs have low molecular weight & are freely filtered from plasma at the glomerulus

• Serum binding ↓ filtration

Question 18

Secretion

Answer 18

Proximal tubule has 2 transport systems that may secrete drugs into ultrafiltrate

• Require energy for active transport against conc. gradient
• Site of potential drug interactions

Question 19

Reabsorption

Answer 19

Reabsorption of un-ionised form of drugs that are weak acids & bases

• By simple passive diffusion
• Rate is determined by:
  
  • Lipid solubility
  • pK
  • Conc. gradient of drug between urine and plasma

Question 20

Renal clearance

Answer 20

Measure volume of plasma cleared of drug per unit time

Question 21

Clearance of a drug excreted by filtration alone (E.g Insulin)

Answer 21

Will have a clearance equal to the GFR

(125-130ml/min)

Question 22

Clearance of a drug excreted by filtration and complete secretion (E.g Insulin)

Answer 22

Will have a clearance equal to renal plasma clearance (650 ml/min)

Question 23

Total body clearance (CL)

Answer 23

Clearance due to renal elimination CLr + clearance due to metabolism CLm

• Renal failure: Clearance of drug may be reduced significantly, resulting in higher plasma levels

Question 24

Hepatic extraction

Answer 24

Occurs because of the liver’s large size and high blood flow

• Extraction ratio is amount of drug removed in liver divided by amount of drug entering organ

Question 25

First pass effect

Answer 25

Oral → Portal vein → Liver → Systemic circulation

Question 26

Drug with hepatic extraction ratio of 1 would have…

Answer 26

0% bioavailability

Question 27

Drug with hepatic extraction ratio of 0.7 would have…

Answer 27

30% bioavailability

Question 28

In the presence of hepatic disease, drugs with high first-pass extraction…

Answer 28

May reach systemic circulation in amounts higher than normal

• May require dose adjustment