Drug metabolism in the liver Flashcards
Explain the basic goals of hepatic metabolism, its role in detoxification, drug activation and where the principle site of metabolism occurs in hepatocytes
• Most drugs are lipid-soluble and this makes them difficult to excrete Therefore, the overall aim of metabolism is to produce a more water soluble compound for excretion (from lipophilic to hydrophilic)
- In general, the metabolism of a drug decreases its therapeutic effect (detoxification)
- However, metabolism of some drugs activate them before subsequent metabolism to inactive compounds (prodrugs)
• Hepatic metabolism occurs in the microsome vesicles of the smooth endoplasmic reticulum (ER) in hepatocyte cells
- The microsomes contain membrane bound enzymes which metabolise drugs.
- The most common enzyme in metabolism is the Cytochrome P450 system.
State where the Cytochrome P450 enzyme is found, its roles in drug metabolism and the importance of its structure in metabolism
- Cytochrome P450 is a hepatic metabolic enzyme found in hepatic smooth ER microsomes
- There are various types of Cytochrome P450 complexes. Over 50 human P450 enzymes have been identified
- Different cytochrome enzymes metabolise different drugs, hence the need for a wide range of CP450
- On its active site, it has a haem-bound iron. This is responsible for binding to and metabolising the drug
- Genetic polymorphisms exist between individuals: different individuals would have genetic variations coding for these enzymes
Understand the outcomes of genetic polymorphism in the genes associated with protein complex, using plasma cholinesterase and acetylation as an example
- Genetic polymorphisms exist between individuals: different individuals would have genetic variations coding for these enzymes
- This alters the way and the rate in which drugs are metabolised in the body between individuals
Plasma cholinesterase:
• Metabolises muscle relaxants
• Certain individuals have a genetic variation in the plasma cholinesterase and this results in significantly slower metabolism of the drug = prolonged neuromuscular blockade
Acetylation:
• Genetic polymorphisms can lead to individuals being fast or slow acetylators
• Slow acetylators are more at risk of dose dependent drug toxicity
Understand the general functions and properties of phase 1&2 reactions in drug metabolism
- Drug metabolism occurs in two phases: phase 1 and phase 2.
- Sometimes the drug metabolism may stop at phase 1, but with most drugs, they continue onto phase 2
- The end goal of phase 2 is to inactive the drug
List the steps involved in phase 1 reactions
- Oxidation
- Reduction
- Hydrolysis
List the steps involved in phase 2 reactions
- Glucuronidation
- Sulphation
- Acetylation
- Methylation
For the oxidation step in phase 1 reactions, use paracetamol and codeine as an example
- Catalysed by the P450 system where a single oxygen atom is inserted onto the drug molecule
- Examples of drugs demonstrating oxidative metabolism; paracetamol and codeine
For the reduction step in phase 1 reactions, state under which circumstance this takes place and use prednisone and warfarin as an example
- Catalysed by the P450 system and only occurs under anaerobic conditions
- Prednisone is reduced to its active drug (pro- drug)
- Warfarin an anticoagulant is inactivated by reduction reactions
For the hydrolysis step in phase 1 reactions, explain why it is unique from the other two steps.
Define context sensitive half life.
- Not catalysed by cytochrome P450 system. Instead, it is catalysed by esterases and amidases
- Amide local anaesthetic agents such as Prilocaine undergo hepatic hydrolysis by amidases
- Hydrolysis can occur in extra- hepatic sites. For instances, it can occur in the plasma as esters exists in the plasma
- Context sensitive half life: The amount of esterases available in different tissues will vary. So, the half life will of a drug will change depending on the amount of esterases that are available at the site
For the glucuronidation step in phase 2 reactions, use Morphine as an example
- Important metabolic pathway for anaesthetic drugs
- While the purpose of phase II reaction is inactivation, Morphine is one exception to this
- Morphine is an already active drug. However, glucuronidation of it makes it more potent
For the sulphation step in phase 2 reactions, use paracetamol overdose as an example
- Sulphation reactions are responsible for the metabolism of about 40% of paracetamol (the other 40% undergoes glucuronidation)
- A small amount turns into NAPQI which is toxic.
- Under normal circumstances, this compound NAPQI is rapidly conjugated with glutathione and is detoxified
- However in paracetamol overdose, the available supply of glutathione runs out quickly
- NAPQI accumulates and is responsible for the resultant hepatic toxicity.
- The treatment of a paracetamol overdose involves giving N-acetylcysteine, a precursor to glutathione.
For acetylation, use genetic polymorphism as an example
- Some drugs undergo acetylation catalysed by the enzyme N- acetyl transferase
- This enzyme has a large degree of genetic polymorphism
- Thus, individuals can be classed as fast or slow acetylators depending on the rate of metabolism of certain drugs
List the physiological and pathological factors that affect drug metabolism
Physiological factors:
• Age (older and neonates have slow metabolism)
• Sex
• Individual variation/genetic polymorphism
• Enterohepatic circulation
• Intestinal flora
• Nutrition
Pathological conditions:
• Aging hepatocytes in liver disease
• Reduced hepatic blood flow in heart failure or shock states
• Kidney disease
State which step of phase I reactions is NOT catalysed by the CP450 system
Hydrolysis
State which drug is NOT inactivated by phase II reactions
Morphine. It becomes more active after glucuronidation
