Drug Metabolism Pt 1 Flashcards
Importance of Drug Metabolism
Importance of Studying Drug Metabolism List A-F
- A. Termination of Drug Action
- B. Bioactivation
- C. Drug Interactions
- D. Stereochemical Implications
- E. Control of Metabolism
- F Metabolism Concept Map
List Phase 1 Reactions. Oxidations (1-6)
- Cytochrome P450
- Aromatic Hydroxylation
- Olefin OxidListation (Epoxidation)
- Aliphatic Hydroxylation
- Heteroatom Oxidations
- Oxidation of Alcohols-Aldehydes-Acids
List Phase 1 Reactions.
Reductions (1-2)
- Aldehyde Reductions
- Ketone Reductions
List Phase 1 Reactions.
Hydrolysis (1-2)
- Ester Hydrolysis
- Amide Hydrolysis
List Phase 2 Reactions. A-C
- A. Glucuronidation
- B. Sulfate Formation
- C. Glutathione Conjugation
List Factors affecting Drug Metabolism
A-J
- A. Cytochrome P450 Multiplicity (isoforms)
- B. Age
- C. Species
- D. Gender
- E. Pregnancy
- F. Environmental Considerations (smoking)
- G. Disease
- H. Enzyme Induction
- I. Enzyme Inhibition
- J. Heredity/Genetics (pharmacogenomics)
Metabolism can terminate drug action by ___(1-3).
- Bio-inactivation
- De-toxification
- E-limination
Example of Bio-inactivation.
Esterase breaks drug molecule into 2 cmpds.
Ex Procaine
Example of Detoxification pathway used in Med Chem.
Antabuse–a planned poison, alcoholic drinks ethanol and he gets sick, due to build-up of aldehyde that is no longer converted to acid.
Example of Elimination.
Acetominophen is converted to sulfate (more polar), then a sugar is added, to make it water soluble and easily excreted.
Expect 90% of Drug Metabolism to lead to …
Termination of Drug Action via:
- Bio-inactivation
- Detoxification
- Elimination
Expect 10% of Drug Metabolism to lead to …
Bioactivation via:
- Active Metabolites
- Prodrugs
- Toxification
Example of Bioactivation.
Imipramine (patented drug) had surprise active metabolite. Imipramine to Desipramine.
2nd company came along and patented Desipramine
Common train of Bioactivation:
Drug Activity goes up and stays up due to active metabolites.
Discover active metabolites via monitoring–PK
Bioactivation can be used to reduce side effects.
Prodrugs are designed to be activated by Metabolism.
Example NSAID. Sulindac (prodrug/less GI upset) a sulfoxide Metabolism reduces to a sulfide, Sulindac Sulfide (active)
Bioactivation can lead to toxicity. Toxigenic Metabolism. Give an example.
MPTP–>MPDP–>MPP+ (neurotoxin. -contaminant in illegal drugs was metabolized into neurotoxin that kills dopaminergic neurons and causes parkinsonism.
Metabolism can also be the cause of Drug Interactions. Give an example involving Warfarin.
Warfarin, blood thinner, can build up if the patient is simultaneously treated with Chloramphenicol (antibiotic) Chloramphenicol blocks CYP450 from breaking down Warfarin (so it stays in system).
What is an example of a stereochemical implication of drug metabolism?
Racemic mixture of Ibuprofen. S-Ibuprofen is active, R-Ibuprofen is inactive. Body inverts R–>S form and you get a kind of prodrug effect. all is good.
Give an example where stereochemical implications lead to toxic effect.
Benoxaprofen is active in S- and inactive in R-. R–>S conversion occurs here. But the elderly do not perform the R-S conversion so R-isoform builds up and becomes toxic.
- This ex. shows that pure S-stereo-isoforms are the best design.
If you can predict metabolic pathways you can:
- avoid toxigenic pathways
- speed up metabolism
- slow down metabolism
Knowledge of the Drug Metabolism is absolutely required by the FDA because:
It clearly affects “efficacy” and “toxicity”
Remember that Chronic Therapy =
Chronic Exposure
