Chapter 8 Drug Metabolism (EXAM 3) Flashcards
Phase I: Purpose of Oxidation reactions
-often needed to expose functional groups -> to add conjugates (Phase II)
-mostly Oxidations (CYP450)
-main enzymes are oxidase & monooxygenases
-found in ER and liver
Phase I: Purpose of Reduction reactions
-Detoxification
Reduction:
-enzymes are very specific (certain functional groups needed for certain enzymes f.e. aldo-keto reductase)
-found in the liver, some in the kidneys, other tissues
Phase I: Purpose of Hydrolysis
-mostly on esters (fast) & amides (slow)
-often in prodrugs to reveal the active drug
-involves non-specific enzymes GI, blood, tissues
What has to be considered in patients with impacted liver function?
Lower the dose bc the drugs are metabolized in the liver
Which aromatic compounds are most likely to be oxidized?
Aromatic hydroxylation:
-Unsubstituted rings (with double bonds) -> epoxide formation -> Hydroxyl group
OR
-electron-donating groups (activating groups)
What need to be considered when choosing the most likely target for Oxidation?
Space -> the more space, the more likely the reaction will occur
Where can an aliphatic carbon be oxidized?
Omega carbon (last)
Omega-1 (second last)
Alpha carbon
Oxidation of Benzyl carbon
-adjacent to an aromatic ring (not much space, but possible -> need a free C adjacent to it)
Oxidation of Alkene
Alkene: involves epoxide intermediate -> Diol formation
Oxidation of Alkyl halide (halogen-containing)
-CYP450 mediated
-oxidative dehydrohalogenation
-ONLY to aliphatic halogens (C-chains), not aromatic halogens
-Add OH -> provides H that leaves with the halogen (HCl) -> and the remaing O forms a ketone
Oxidation of Amines (NH2)
amines are common, so many enzymes involved
-Oxidative deamination: Add OH -> NH3 leaves -> Keton formed
-N-Oxidation: adding O(-); the N will be charged (+) -> unstable metabolite
-Dealkylation: losing methyl groups from nitrogen
-> Add OH to the alkyl -> loss of the alkyl in the form of an aldehyde
Oxidation of 1° Alcohols
Oxidation of 2° Alcohol
1°OH -> Aldehyde CHO -> possibly to COOH
-driven by alcohol dehydrogenase
2°OH (aldehyde - COH) -> Keton (no space for further oxidation to COOH because only 2 R -> wich is why it is 2°)
Oxidation of 1° Alcohols
Oxidation of 2° Alcohol
1°OH -> Aldehyde CHO -> possibly to COOH
-driven by alcohol dehydrogenase
2°OH (aldehyde - COH) -> Keton (no space for further oxidation to COOH because only 2 R -> which is why it is 2°)
Oxidation of Ether
Oxidation of Thioether
O-Dealkylation: Ether is getting dealkylated -> OH and Aldehyde
S-Dealkylation: Thioeter is getting dealkylated -> SH and Aldehyde
Why are Esters often used as prodrug instead of Amides?
Because the hydrolysis in esters is faster
