ADME 7 Flashcards
what is Phase I Metabolism Functionalization?
Introduction of polar functional groups into molecules- usually by addition of oxygen
what does phase 1 metabolism functionalization require?
Require NADH or NADPH (electron source) and O2as cofactors
•NADPH-P450 reductase(or cytochrome b5) enzyme used as electron carrier
where are Mixed function oxidases or monooxygenase located?
liver- in the endoplasmic reticulum
where does oxidation most dominantly occur in aromatic rings?
in electron rich system- OH usually introduced in para position
what prevents or slows oxidation?
electron withdrawing groups (e.g. Cl, N+R3, COOH, SO2NHR) slow or prevent oxidation
what is Benzo[a]pyrene?
Polycyclic aromatics –common constituents of soot, tars, car exhausts, burnt foods–Benzo[a]pyrene
–the first isolated carcinogen
what are the oxidation of alcohols and aldehydes catalyzed by?
Catalysed by non-microsomal dehydrogenases–alcohol dehydrogenase
–aldehyde dehydrogenase
what is a benzylic carbon?
benzne ring with a carbon directly attached
if you oxadize a primary methyl benzylic what do you get?
primary alcohol
what is an allylic carbon?
C adjacent to a C=C
what is a saturated carbon?
Occurs in drugs with straight or branched alkyl chains
where does oxidation occur in a saturated carbon?
Oxidation at terminal methyl groups –“omega” (w)
•Oxidation at the next to the last carbon –“omega –1” (w-1)
inserts a hydroxyl
what happens in the oxidation of a carbon to a heteroatom?
Oxidation of carbon attached to O, S, N
–also termed N-, O-,S-dealkylation
–note initial oxidation of C-H followed by elimination
what are secondary amines subject to?
Secondary amines subject to N-dealkylations, oxidative deamination, and N-oxidations
•N-dealkylation proceeds similar to tertiary amines
what does Insertion of oxygen into an N-H bond leads to?
N-oxidation
For primary amines on a tertiary carbon:
OnlyN-oxidation possible as an a-carbon oxidation is not available
how are aromatic amines generated?
reduction of nitro groups (Ar-NO2-> Ar-NH2)
•reductive cleavage of azocompounds (Ar-N=N-R -> Ar-NH2)
•hydrolysis of aromatic amides (Ar-NHC(=O)R -> Ar-NH2)
what do primary aromatic amines give?
give N-hydroxyl and nitroso compounds
what do tertiary aromatic amines give?
N-dealkylations, N-oxides
what do secondary aromatic amines give?
secondary aromatic amines: N-dealkylations,
N-hydroxylations
•both relatively rare in drugs
what is desulfursation?
Desulfurisation: C=S conversion to C=O
what is the Hepatic Microsomal Flavin Containing Monooxygenases?
Present in endoplasmic reticulum of liver cells
•OxidisenucleophilicSand NFGs
•Different mechanism to Sand Noxidation by CYP450, but products are similar
where is MAO-A found?
MAO-A is found in the adrenergic nerve endings
where is MAO-B found?
platelets
what does the brain contain mostly- A OR B
MAO-B
What does MAO-A have selectivity for?
MAO-A has selectivity for serotonin, epinephrine, norepinephrine and 5-hydroxytryptamine, and other monoamines with phenolic aromatic rings
what does MAO-B have selectivity for?
MAO-B has selectivity for non–phenolic amines
what kind of enzymes catalyze most reductions?
CYP450 enzymes
what do aldehydes and ketones reduce to?
Aldehyde and ketones give 1o and 2o alcohols,
what do nitro and azo reductions give?
Nitro and azo reductions lead to amino derivatives
Reduction of N-oxides ?
Reduction of N-oxides to corresponding 3oamines
Reduction of sulfoxides?
Reduction of sulfoxides to sulfides
