Drug Metabolism Flashcards
What is a xenobiotic
a substance found within an organism that is not usually found within the organism
what is the normal polarity of a xenobiotic
non-polar
What do we do to xenobiotics to excrete them and why
we manipulate them to become polar so they can be readily excreted
where does metabolic transformation primarily occur
in the liver
what is first pass metabolism
the amount of a substance that is metabolised by the liver the first time it enters the liver from the gut
What types of reaction can you get in phase I of metabolic transformations (3)
Oxidation, reduction and hydrolysis
what types of reactions can you get in phase II of metabolic tranformationa
Glucoronidation, amino acid or glutathione conjugation, sulphation, acetylation and methylation
which phase of metabolic change changes the polarity of a drug
Phase II
Are both phases compulsory? If not which one is
Neither are, sometimes only phase I or sometimes only phase II
In cytochrome P450 mediated oxidation, if the drug is:
RH + NADPH + O2 + H+
What’s the oxidised drug?
ROH + NADP+ + H2O
In cytochrome P450 mediated oxidation, if the oxidised drug is:
ROH + NADP+ + H2O
What’s the reactants drug?
RH + NADPH + O2 + H+
What does hydrolysis do in phase I
Unmasks 2 functional groups
What do the functional groups revealed in phase I do in phase II
serve as attachment points for phase II reactions
When is cytochrome P450 used?
Phase I of metabolic transformations
What does phase I usually do to drugs? When is the exception?
Inactivates them, in the case of prodrugs can activate them
Drug binds to CYP450, what happens next
Drug binds to the iron in the catalytic site and a NADPH donates an electron. This reduces Fe3+ to Fe2+. Oxygen then binds to CYP450. The Fe2+ reduces oxygen, and then Fe3+ is reduced again by NADPH and this again reduces oxygen making it very unstable. The drug is then hydroxylated by one of the O2’s and we lose the other oxygen as water by picking up 2 protons.
What is used during CYP450 oxidation
2 NADPH’s for their electrons, 2 hydrogens and an O2
What does oxidation do to N-methyl or O-methyl groups
It removes HCHO (formaldehyde), AKA demethylation
What is N-oxidation
Donating the lone pair of electrons on nitrogen to an oxygen
Which oxidation uses different enzymes rather than CYP450
N-oxidation and alcohol oxidation, which uses alcohol dehydrogenase
What type of enzyme does reductions
Reductases
Where do the majority of our reductase enzymes come from
bacteria in the GI tract
Which molecules does hydrolysis occur to
Esters and amides
What enzyme does glucoronidation
Glucoronyl transferase
What enzyme does acetylation
acetyl transferase
What enzyme does amino acid conjugation
Acyl transferase
What enzyme does methylation
Methyl transferase
What enzyme does sulphation
Sulphotransferase
What enzyme does glutathione conjugation
Glutathione-S-transferase
What drug is pharmacologically active after conjugation
Morphine, morphine glucuronide is still active
why does conjugation make drugs easier to excrete
the huge polar group added to it makes it less lipid soluble
What is the main defence mechanism of the body to get rid of harmful chemicals (free radicals and electrophiles)
Glutathione
What is the conjugating agent for glucuronidation
UDP-glucoronic acid
What is the conjugating agent for acetylation
Acetyl CoA
What is the conjugating agent for amino acid conjugation
Glycine, glutamine, taurine
What is the conjugating agent for methylation
S-adenosyl methionine
What is the conjugating agent for sulphation
3’-phosphoadenosine-5’-phosphosulphate
What is the conjugating agent for glutathione conjugation
Glutathione
Which type of phase II reactions occurs the most
Glucuronidation
What elements does acetylation and methylation target (3)
N, O, and S
What is the target functional group for glucuronidation (4)
OH, COOH, NH2, SH
What is the target functional group for acetylation (2)
OH, NH2
What is the target functional group for amino acid conjugation
COOH
What is the target functional group for methylation (2)
OH, NH2
What is the target functional group for sulphation (2)
OH, NH2
What is the target functional group for glutathione conjugation
electrophiles
