Drug metabolism Flashcards
(52 cards)
Outline the requirements for CYP mediated oxidation reaction (phase I)
Drug
Cofactor for reduction (NADPH/NADH)
Molecular oxygen
Protons
What are the products of a CYP ocidation reaction
Oxifised drug
NADP+
H2O
What is the common structure of cytochrome enzymes
Porphyrin ring with iron in the middle CATALYTIC
Explain how the cyt p450 causes oxidation of a drug
Drug binds at the site of the porphyrin ring containing catalytic iron. Interacts with Fe3+
NADPH or NADH provides an electron. That electron is picked up by iron at the active site. Fe3+–> Fe2+
Oxygen added, which binds at the active site (near the iron and the drug). The electron that the iron gained from the NADPH is now transferred to the oxygen. Iron converts back Fe2+–>Fe3+
Electron makes oxygen aggitated
Another electron is then picked by the iron. Fe3+–>Fe2+
Another electronic rearrangement. Fe3+–>F2+ again. Second electron picked up by the molecular oxygen which is now very unstable
One of the O molecules from molecular oxygen reacts with 2 protons to become water. The other O molecule reacts with the drug to form the hydroxyl group
Substrate released
T/F for the oxidation of the drug with Cyt p450, only 1 NADPH was needed
F…. 2 were needed. 1 molecular oxygen needed
Which molcules can be used as reducing agents in cytp450 reactions
NADPH or NADH (sometimes)
T/F cytp450 involves hydroxylation
T! It is an oxidation reaction BUT
Oxidation reactions generally start with a hydroxylation step
catalysed by the P450 system.
Which step in CYTP450 oxidation is rate limiting
The second reduction
T/f all compounds are oxidised in the same position with CYTP450
f…..
in aliphatic compounds e.g. pentobarbitone (a barbiturate), OH group added in any of the carbons
there is a main metabolite (pictured)
-OH added.
What is acetanilide
It is an aromatic structure
Oxidised by CYTP40
When oxidised forms paracetemol
(-OH added)
but this is not sold as a pro-drug because it is toxic for blood cells
What is N-demethylation
Oxidation of carbon ATTACHED to nitrogen (this tertiary nitrogen acts as substrate for the cytp450)
Oxidised N-methyl group.
Formaldehyde drops off (HCHO), and a proton gained.
e.g. Imipramine (tertiary nitrogen) –>desimipramine
What is O-demethylation
Oxidise carbons attached to oxygen.
Formaldehyde again drops off (HCHO)
e.g. CODEINE TO MORPHINE (in this reaction, happens very well insome people and no tin others due to differing CYTP450)
What is N-oxidation
This is oxidation of the nitrogen group on a teritary nitrogen with lone pair of electrons (trimethylamine)
Lone pair of electron on the nitrogen- it donates it to an oxygen
Makes amine oxide (oxide of tertiary amines)
NOT BY CYTP450 by flavine containing monooxygenase
What occurs in people with low flavine contianing monooxygenase
This is a polymoprhic enzymes so differing amounts
In N-oxidation, the substrate is a tertiary nitrogen with lone pair of electrons.
Smells like fish
Flavine containing mono-oxygenase allows donation of the lone pair of electrons to an oxygen
In people with low levels, the teritiary nitrogen with lone pair accumulates (the trimethylamine), and they smell bad.
FISH ODOUR SYNDROME
Is there a cure for fish odour syndrome
No
Have to avoid trimethylamine
But it’s everywhere including when eating meat in choline which is converted to trimethylamine
High rates of suicide etc.
Outline oxidation of ethanol
Ethanol –> acetaldehyde by alcohol dehydrogenase
Acetaldehyde –> acetic acid by aldehyde dehydrogenase
NOT CYTP450
REVERSIBLE
Differentiate ethanol metabolism to most other metabolism
Alcohol dehydrogenase is zero order kinetics.,
Most other enzymes (CYTP450, flavine containing monopoxygenase) are 1st order
T/F CYTP450 is not a reductase
Mostly true, but can act as a reductase very rarely in some circumstances
Where do reductase reactions occur (phase 1)
GI tract by bacterial reductases
e.g. prontosil –> sulphanilamide
prontosil is an antibacteria drug, but of a non antibiotic type. Can’t be used against gut bacteria
T/F oxidation and reduction happen in equal meausre
F… reduction far less common than oxdation
When does hydrolysis of a drug occur
What enzymes
What are the products
On esters or amides
e.g. procainamide
ESTERASES and AMIDASES
Products include COOH and amino groups
T/F xenobiotic metabolism only happens in the liver
F
Phase 1 metabolism can introduce functional groups such as what
–OH, -NH2, -SH or –COOH.
act as handles for phase II metabolism
T/F most of the products of phase I are biologically inactive
T
