3.1:9 Metabolism of drugs Flashcards
How are drugs eliminated from the body?
Excretion and metabolism (major route)
What are the most common metabolic reactions ?
Oxidation, reduction, hydrolysis and conjugation
What is sequential metabolism?
Further (secondary) metabolism ie conjugation reaction. These reactions occur in series
What is competitive metabolism?
When a drug simultaneously undergoes metabolism by several competing (primary) pathways.
The fraction depends on the relative rates of each pathway.
What are phase I reactions?
Reactions that often occur first (oxidation,reduction and hydrolysis)
Phase I reactions are commonly considered to be preparation of the drug molecule for phase II
What are phase II Reactions?
Reactions that often occure second (conjugations)
What are chytochrome P450-dependant mixed-functional oxidation (MFO) reactions ?
They cataluse the oxidation of many drugs and chemicals
Metabolised molecule usually has a reasonably high degree of lipophilicity
What is the percentage of similarity in a the cytochrome family
40%
What is the percentahe opf silimarity in the cytochrome sunb-family ?
70%
Where is CYP3A found ?
Highly active in the small intestine (especially duodenum) and much less in the large intestine
State the oxidations involving CYP450
- Aromatic hydroxylation
- Aliphatic hydroxylation
- Epoxidation
- Dealkylation- N,-O, -S
- Oxidative deamination
- Dehalogenation
- N-oxidation
- S-oxidation
- Phosphothianate oxidation
What enzyme is used to convert ethanol to acetaldehyde?
Alcohol dehydrogenase 1B
True/False . Acetaldehyde is a highlt unstable compound and forms free readical structures which are highlt toxic
True
What enzyme is used to convert acetyldehyde to acetic acid ?
Alcohol dehydrogenase 2
What do 1/3 of east asians lack and what is the result of this?
Alcohol flushing response
Alcohol dehydrogenase 2 resulting in prolonged period of time of acetaldehyde in their system.
This causes extreme toxisity to the body and can damage the body
Name a reductive metabolism
Azo-compounds
Nitro-compounds
Hydrolysis
Amide hydrolysis
In phase I metabolism what functional grtoups do the final products usually have ?
-OH, -NH2, -SH, -COOH (these are ready to react for phase II)
Why is it difficult to predict the exact pathway of a drug?
Drugs can undergo a number of phase I reactions therefore it is really difficult to predict the exact pathway from their chemical structure
What do phase II metabolism generally lead to ?
Water soluble products which can be excreted in bile and urine
What is the major route of sugar conjugation?
Glucuronidation (conjugation with a- D-glucuronic acid)
What is the difference between:
a. UDP-Glucuronosyltransferase (UGT)
b. UPD-glucuronic acid
a. Enzyme
b. Co-factor
Name the phase II pathways
O- Glucuronidation N-Glucuronides Sulfation Acetylation Aminoiacid conjugation
What ios the difference between sulfation and Glucuronidation?
Most drugs that can be glucuronidated, can also be sulfated which leads to a possibility of competition for the sunstrate between these two pathways
Sulfate conjugation predominateds at low subsrate conc where as glucuronide conjugation predominates at high concentration
True/false? The liver is the mainorgan responmsible for phase I and pahse II metabolism ?
True but other organs are involved in drug metabolism
What does drug localisation and metabolism depend on?
Physiochemical properties of the drug (pKa, lipid solubility, MW)
Chemical composition of a metabolising organ
Presence of specific uptake mechanism (transporters)
