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What is the toxic metabolite of Acetaminophen
N-acetylimidoquninone
What is the biologically active metabolite of diazepam
Diazepam to Oxazapem
Example of progrug
Protonsil to Sulfinamide
What groups are added in a phase 1 metabolism
OH, COOH, SH, NH2
What are the types of Phase 1 reactions
Reduction, Hydrolysis and Oxidation
What are the Phase 1 reduction reactions
Azo Reductase, Nitro Reductase, Aldo-Keto Reductase
What are Phase 1 Hydrolysis reactions
Amide and Ester reactions
What enzymes are used for clinically relevant drufs
CYP3A and CYP2C
What enzyme is used for enviornmental substances
CYP1A2
What happens in an oxidation reaction
CH-COH
How is increased stability reached in oxidation
Ch to CF
What are the priveleged hydroatom spots
Alpha, allylic, benzylic and heteroatom
What happens in dealkylation
Ch3 to H
What happens in deamination
Amine to ketone
What happens in N oxidation
Becomes an N oxide
What happens in O delakylation or oxidative dealkylation
ROR to ROH
What happens in S dealkylation
RSR to RSH
What are MFOs
Enzymes resposible for addition and removal of Oxygen into drug molecules
What are microsomes
Materials used for in vivo testing
What do MFO enzymes require
NADPH and Molecular Oxygen
What does oxidation of primary alcohols lead to
Aldehyde then COOh
What does oxidation of secondary alcohol lead to
Ketonea
What does oxidation of tertiary alcohol lead to
Cannot be oxidized
What is Alkyl side chain hydroxylation
Omega and Omega -1
What is N hydroxylation
Adding OH to 1, 2 and 3 amine
What happens to tertiary amine in N hydroxylation
Becomes N oxide which is neutral
What happens in oxidation of thioethers
Becomes Sufoxide then Sulfone
What happens in Oxidative desulfurization
X=S becomes X=O
example of oxidative desulfurization
Malathion to malaxion
What happens in Oxidation of Olefins
Double Bond becomes epoxide
What happens in oxidation of allylic and benzyllic carbons
the carbon becomes an OH
What happens in hydroxylation of aromatic ring system
Becomes an epoxide then an arene oxide at the para position
What are the fates of arene oxides
Phenol
Bind to Protein
Bind to H20
Bind to GSH
What do Flavin containing monooxygenase system do
Oxidizes compounds with nitrogen and sulfur
What do Monoamine oxidases do
Catalyze oxidative deamination of endogenous catecholeamines
What are monoamine oxidases inhibited by
Antidepressants known as MAO inhibitors
What are the intermediates of Azo reduction
Hydrazo intermediate
What is a Nitro reduction intermediates
Nitroso and Hydroxylamine intermediates
What happens in Nitro reduction
Nitro group becomes amine
What happens in Azo reduction
N =N becomes Nh + Nh
What happens in Aldehyde reduction
Aldehyde becomes primary alcohol
What happens in Ketone reduction
Ketone becomes secondary alchol
What happens in Ester Hydrolysis
Ester becomes Alcohol and Carboxylic acid
What happens in amide hydrolysis
Amide becomes amine and carboxylic acid
How to form iminoquinone
Need to have benzene ring with N
Need to have CH or OH opposite of N
What happens after Iminoquinone is formed
attaches to GSH and goes through glutathione conjugation.
What is the most common conjugation reaction in phase 2 metabolism
Glucoronic Acid Conjugation
What are the affects of Glucornic acid conjugation
Increased water solubility
How is UDPGA formed
Glucose + UTP with UDGP dehyrogenase enzyme
What forms in O glucornidation when theres an alcohol as the substrate
OH → ROR
What forms in O glucornidation when theres a carboxylic acid as the substrate
COOH → ROOR(ester)
What forms in N glucornidation
Primary → secondary amine and secondary to 3
What forms in S glucornidation
Sh → Thioether and
Thiol Acid → Thioester
What forms in C glucornidation
glucornic acid attaches to the carbon
What are the substrates of Sulfate conjugation
Phenol and Catecholamines
What forms in Sulfate conjugation
OH→ OSO3H
Where does sulfate conjugation put SO3
on the 3’ position
What enzyme and coenzyme are used for sulfate conjugation
enzyme= Sulfotransferase
Coenzyme= PAPs
What enzyme and co enzyme is for Glucornidation
Coenzyme= UDPGA
Enzyme = UGt
What forms in Acetylation
Amine is changed to Acetyl group
What are the coenzymes and enzyme for acetylation
Enzyme= acyltransferase
Coenzyme= acetyl coa
What are the substrates for acetylation
Amino, Hydrazine, Hydrazide, sulfonamine
What is added in humans in Amino Acid Conjugation
Glycine and Glutamine
What are the enzyme and coenzyme in Amino acid conjugation
Enzyme= N acyl transferase
Coenzyme= Acyl coenzyme intermediatw
What are the substrates of Amino acid conjugation
Carboxylic acid
What forms in amino acid conjugation
Carboxylic acid—> Amide and carboxylic acid
What are the substrates of methylation
Phenols, Catechols and enzymes
What are the enzymes and Coenzymes in Methylation
SAM, Methyltransferase
what is the enzyme for phenols in methylation
COMT
What is the enzyme for catechols in methylation
PNMT
What forms in methylation
OH→ OCH3 or NCH3
What is the driving force of glutathione conjugation
Reactivity of sulfhydryl group
What are the derivatives of GSH conjugation
Mercapturic acid
Why is mercapturic acid formed
GSH cannot be excreted so needs to be converted to mercapturic acid to be excreted
What are the enzymes involved in mercapturic acid formation
glutamyltranspeptidase
Cysteinylglycinase
N-acetylase
What are the substrates of Glutathione conjugation
Micheal Acceptor
Epoxide
Iminoquinone
What happens if metabolic clearance is increased
The drug does not last long in the body
decreased efficacy of drug
decreased action of drug
What happens if metabolic clearance is increased
Toxicity of drug in body
Prolonged action of drug in the body
How do drugs affect newborns differently
Newborns are deficient in UDPGA which leads them to not synthesize bilirubin and leads to Gray baby syndrome
How do drugs affect geriatric patients
They have decreased metabolism of drugs such as quinidone
What happens to Phenytoin in humans vs animals
The OH goes onto the bottom phenol instead of the other one
What do humans use in conjugation vs other species
Glycine and Glutamine vs birds use ornithine
Why are there acetylation rate differences among humans
Because of N acyltransferase activity
What happens with enzymes that causes gentic variability
Genetic Polymorphism
What drugs are metabolized faster in woman
Diazepam, Predinisolone, Caffeine, Acetamminophone
What drugs are metabolized faster in men
Zolpidem, Proponal, Lidocaine and Chlordiazepoxide
What inhibits Warfarin
Phenylbutazone
What inhibits the metabolism of tobumalide
Dicoumerol, chloramphenicol and phenylbutazone
What does grapefruit juice inhibit
CYP3A4 leading to decreased metabolic clearance
What is SKF 525A
An inhibitor of CYP450
What does induction of CYP system lead to
Decreased drug action and faster clearance of drugs
What does enzyme inhibition do
Slower clearance of drugs
How does stereochemistry affect drug metabolism
Enantiomers can get metabolized differently.
When you have 3 heteroatoms next to each other which one is more likely to get dealkylated
T
