Drug Metabolism and Elimination

Question 1

What is drug metabolism?

Answer 1

It is the removal of lipid-soluble drug molecules to prevent their reabsorption by the kidneys. This is achieved by converting the drugs into water-soluble molecules.
It occurs mostly in the liver, but some may also occur in the plasma, lung and intestinal epithelium.

Question 2

What is drug excretion?

Answer 2

It is the removal of drugs/metabolites from the body.

This is done mostly by the urine, but also via bile/faeces, sweat, tears, saliva, exhaled air and milk.

Question 3

What is the clearance for a drug that is removed by liver metabolism and kidney excretion?

Answer 3

Plasma CL = Hepatic CL + Renal CL

Question 4

Why is drug metabolism and excretion important?

Answer 4

DOSING ISSUES:

• metabolism/ clearance determine the amount of drug available at the site of action
• time taken for a drug to reach steady state levels

SAFETY ISSUES:

• metabolism produces new chemical entities that may have their own effects
• components of racemic molecules (D/L) handled differently

Knowledge can aid the design of future drugs.

Question 5

Briefly, describe drug metabolism.

Answer 5

The removal of a drug begins immediately. Most of them undergo metabolism prior to removal to increase excretion. There is a loss of (or reduced) biological activity to increase the polarity of the drug or decrease the receptor binding.

Some drugs are activated by metabolism (eg. enalapril is converted into its active form enalaprilat by esterases), while some drugs are eliminated unchanged.

There are two stages of drug metabolism.

Question 6

Describe the two stages of drug metabolism.

Answer 6

PHASE 1 (makes drug more reactive to other metabolic pathways)
Phase 1 introduces chemically reactive groups. The main process is oxidation within the liver. This is the addition of oxygen molecules to carbon, nitrogen, sulphur molecules in the drug structure.

It’s carried out by cytochrome P450 enzymes (a huge superfamily of enzymes in the liver)

• binds the drug and the oxygen molecule
• oxidation of the drug occurs through one oxygen atom, the other is reduced to water

PHASE 2 (gets molecules attached to drugs)
Phase 2 increases the water solubility of the drug for excretion.

It conjugates (connects) the Phase 1 product with an endogenous (internal) substance through the production of stable covalent bonds (eg. glucuronidation, reaction with glucose)

Question 7

Describe the important exception to the 2-phase metabolism rule.

Answer 7

The metabolism of paracetamol is an exception to the 2-phase rule.
Normally, drugs go through phase 1 then phase 2; however, paracetamol metabolism takes it straight to phase 2. This adds a glucose or sulphate group onto the end of it, instead of a hydroxyl, and this converts the paracetamol into two water-soluble, benign conjugates that will be excreted readily by the kidney.
If you were to have too much paracetamol, the other two processes would be saturated, meaning that it would go through phase 1 first. The cytochrome P450 then creates a toxic intermediate. This toxic substance is very reactive and will bind to your body’s proteins, changing their shape, thus altering their effectivity.

Question 8

Describe drug excretion by the kidney.

Answer 8

1) GLOMERULAR FILTRATION
It filters <20kDa molecules. The amount excreted depends on the levels of the drug bound to plasma proteins.

2) TUBULAR SECRETION
Acid/base molecule carriers transport molecules into tubular fluid. This lowers the levels of unbound drugs in the plasma, pushing the reaction for plasma proteins to release more free drugs for secretion by carriers.

3) TUBULAR REABSORPTION
As molecules pass through tubules, they are concentrated, creating large concentration gradients for reabsorption (hence the need to make drugs water-soluble).

EXCRETION = FILTRATION – REABSORPTION + SECRETION

Question 9

What is renal clearance?

Answer 9

It is the volume of plasma cleared of the drug per unit time in one pass through the kidney. The drug is cleared from the blood and appears in the urine.

A decrease in renal clearance increases the drug’s plasma half-life.

Question 10

What factors affect drug metabolism and excretion?

Answer 10

AGE

• Cyto P450 activity is reduced in neonates/elderly people
• GFR (Glomerular Filtration Rate) is reduced greatly in neonates/elderly
• There’s an increased percentage of fat content in elderly people

GENETICS

• 45% in Europe & USA; 80-90% Asians fast acetylators
• 1/3000 slower metabolism by pseudocholinesterase

DRUG METABOLISING ENZYMES

• Can be induced by other drugs or lifestyle factors
• Can be inhibited by some drugs

DISEASE

• Liver disease impairs drug metabolism - drug toxicity
• Renal disease may alter pharmacokinetics

Question 11

Why do we monitor drug concentrations?

Answer 11

• for drugs that have a narrow therapeutic index
• for drug concentrations that relate well to either therapeutic effect or toxic effect, or both
• to individualise therapy
• to confirm adherence of therapy
• to diagnose toxicity
• to determine the presence of other drugs before starting therapy (e.g. theophylline in an unconscious patient with asthma)
• as part of post-marketing surveillance to detect drug-drug interactions