Liver and basic drug metabolism Flashcards
what is the ultimate goal of metabolism?
Ultimate goal is to convert lipophilic substances into more polar and hence more excretable metabolites.
______ reduces exposure to potential toxicity
metabolism
what are the results of the transformation of lipophilic substances during metabolism?
list 4
More polar metabolite created - ionisable group added
Mol. wt and size often increased
Excretion facilitated
Elimination increased
The liver - primary importance for most drugs because______
list 2
Compounds absorbed from the GIT pass through the liver before entering the circulation
High levels of drug metabolising enzymes
what are 5 consequences of metabolism?
Biological half-life is decreased
Duration of exposure is reduced
Accumulation in the body is avoided
Biological activity may be changed
Duration of the biological activity may be affected
how many phases of metabolism?
2
what happens in phase 1 of metabolism?
Introduction of a functional group in order to:
Increases polarity
Creates site for conjugation reaction
what happens in phase 2 of metabolism?
Conjugation of a hydrophilic group in order to:
Increases solubility
Enhances elimination
list the main enzymes involved in phase 1 metabolism?
Hepatic mixed function oxygenase (MFO) system:-
Cytochrome P450 and FMO.
list 3 other phase I enzyme system
alcohol dehydrogenase,
xanthine oxidase (uric acid synthesis),
monoamine oxidase (5-HT, noradrenaline)
list most important enzyme for phase 1 drug metabolism?
cytochrome P450 families 1-4:
CYP1; CYP2; CYP3; CYP4
MFOs have _______substrates as well
endogenous
list 4 facts about cytochrome P450.
Haemoproteins - (apoprotein with a heme prosthetic group)
Located in the membrane of the endoplasmic reticulum
Act in concert with electron donors
(NADPH reductase
Cytochrome b5 reductase)
Movement of charge and electrons across the complex is vital for the catalytic site to function.
list the enzyme responsible:
Ethanol __ Acetaldehyde
Paracetamol __ hepatotoxic metabolite.
Tolbutamide ___ excreted metabolite
CYP2E1
CYP2E1
CYP2C10
_____is the most abundant P450 in human liver
Cytochrome P450 3A4
> 50% of drugs in clinical usage today, that are oxidised, are _____
substrates
_____is the most common metabolic reaction, including hydroxylation and dealkylation.
Oxidation
________is less common than oxidation reactions - microsomal enzyme system reactions.
reduction
what happens with warfarin in reference to phase 1 reaction??
Warfarin - ketone group to a hydroxyl group
what happens with Chloramphenicol in reference to phase 1 reaction??
Chloramphenicol – nitro group to amine group
________ is relying on a ‘handle’ i.e. a reactive group to form a inactive and readily excretable compound
Conjugation reaction
Addition of a conjugate increases hydrophillicity
list 5 conjugates
Glucuronic Acid
Sulphate
Amino acids (Gly)
Glutathione (Glu-Gly-Cys)
Acetylation
Multiple different enzymes involved
Drug metabolite should now be polar enough to be excreted via urine/faeces.
are all in which phase of metabolism
phase 2
_______ is common conjugation reaction for a wide range of substrates.
Glucuronidation
give an example of glucuronidation.
Involves transfer of activated form of glucuronic acid - paracetamol
Many drugs undergo sequential ________and then ______________
e.g. - Aspirin - salicylic acid – glucuronide conjugate
phase I
phase II
