3a. Metabolism - ADME II: elimination of drugs Flashcards
what is metabolism
biotransformation of drugs
enzyme mediated chemical change to the drug molecule, either building molecule up or breaking down
parent (unchanged) -> metabolites
how does metabolism help drug elimination
altering chemical structure of molecule often means its ability to move around the body is altered so its easier to excrete or a change in its effects making its ability to bind to receptors (making it inactive)
many drugs are lipophilic to aid what and what does this means for elimination of parent form
lipophilic o aid absorption and distribution = high reabsorption in kidney and poor elimination in their parent form
metabolism produces more ___ metabolites that are better/harder excreted from body
hydrophilic polar meetabolites
better excreted
does metabolism abolish activity of drug
usually but not always
what are the 3 things that drug metabolism can result in
promotion of activity
no change
toxic
what is metabolism resulting in promotion of activity
drug metabolized to metabolites that are more pharmacologically active
what is metabolism resulting in no change in activity
metabolite formed is equally biologically active as parent drug
what are the 5 major sites of drug metabolism
liver intestinal wall GI tract plasma lungs
why is the liver a possible site of drug metabolism
high levels of metabolising enzymes
why is the intestinal wall a possible site of drug metabolism
CYP450 enzymes
why is the GI tract a possible site of drug metabolism
gut bacteria and proteases
why is the plasma a possible site of drug metabolism
esterases - prodrug activation
why is the lungs a possible site of drug metabolism
metabolism of aerosol sprays
what happens to drugs administered orally in the part of the organs
what effect does metabolism in the digestive organs have on bioavail
Drugs administered orally will need to traverse GI tract, move across gut wall pass through portal vein and reach liver before reaching systemic circulation
Metabolism that occurs during this passage means not all oral dose is absorbed
Some orally admin drugs may greatly affect bioavailability by first pass that diff routes must be used to achieve therapeutic levels
what does first pass metabolism affect
affects the bio avail/fraction of dose that will reach systemic circulation
can drugs adminstered in IV form still udnergo metabolism
cant occur with first pass metabolism but can undergo systemic metabolism
first pass metabolism is before/after systemic circualtion
before
systemic metabolism is before/after systemic circualtion
after
what are the 4 types of metabolism reactions
oxidation
reduction
hydrolysis
conjugation
what is an oxidation metabolism reaction
increase proportion of oxygen on the molecule
what is an reduction metabolism reaction
loss of oxygen
what is an hydrolysis metabolism reaction
water molecule is added to compound usually resulting in bond cleavage
what are the 3 functionalization reactions for metabolism and what do they all do
create/modify a functional group
oxidation, reduction, hydrolysis
what is conjugation metabolism reaction
addition of endogenous substrate
what are the 4 types of conjugation metabolism reaction
glucuronidation
sulphataion
acetylation
glutathionylation
what does conjugation metabolism reactions do to the molecular mass, polarity and excretion
increase molecular mass
polarity/water solubility increase
increase likelihood of excretion
what are the phase 1 reactions
oxidation, hydrolysis and reduction
what is a phase 2 reaction
conjucation
functionalisation reactions can result in metabolites that are more prone to what
more prone to undergo conjugation reaction
what is the misconception about phase 1 and 2 reactions names
phase 1 isnt always before phase 2
what are the 4 paths that a parent drug can take regarding functionalization and conjugation reactions on their way to excretion
is it as simple as this?
1/ parent drug -> functionalisation and then excretion
2/ parent drug -> function -> conjugation -> excretion
3/ parent drug -> exception
4/ parent drug -> conjugation -> excretion
not as simple as sometimes conjugate metabolite forms from conjugate reaction can be substrate for another functionalization
what is the most important functionalisation reaction
oxidation
what is the enzyme that facilitates oxidation
CYP450
what are the 3 families of CYP involved with drug metabolism and how many isoforms are responsible for majority of phase 1 reactions
CYP1,2, and 3
4 isoforms
what 3 things does exidation require and which is the reducing agent
O2, NADPH (reducing agent), cytochrome p450
what is the nomenclature of CYP family eg CYP3A4
C = cytochrome P = P450 wavelength 3 = family A = subfamily 4 = isoform
what are conjugation reactions
synthetic reactions as it involves adding an endogenous molecule onto drug
what is the endogenous molecule in a conjugation reaction normally
carbohydrate, an amino acid or something derived from the 2
what does conjugation reactions do to the property of the molecule
makes it larger
increase water solubility
what is glucouronidation and what compounds is it common for
endogenous compounds and drugs
what is the key enzyme for glucouronidation
UGTs
what does UGTs do
transfer polar glucose derivative onto target molecule
what is sulfonation carried out by
sulphotransferases
what are major areas of high activity for sulphotransferases
SI, colon, liver, pancreas
what does sulfonation do to the property of molecule and what is this good for
increases water solubility of molecule
improves excretability in bile and urine
what do sulphotransferase transfer
sulphonate from donor PAPs onto acetyl or hydroxyl group of receiving molecule
what is a limitng factor for sulfonation
PAPS is synthesised in all almost all tissues but its depletion limits sulfonation
for sulphotransferases what are forms associated with the cell membrane involved in
housekeeping
what is glutathione conjugation done via
glutathione S transferases
what does glutathione conjugation do
clean up system for reactive species generated in cells as well as other functions
what does acetylation do to the properties of the compound and what does this achieve
generally decreases water solubility so that its more difficult to excrete metabolites in the urine
what functions does acetylation have
housekeeper and homeostasis
what does methylation do
adds lipophilic methly group to decrease water solubility
what is methylation used for in terms of the types of compounds it facilitates
small endogenous compounds
why are there variations seen in metabolism
drug dose required to achieve effective therapeutic blood levels can be diff in diff people
metabolism rate in people
genetic and non genetic factors
what will extensive and poor metabolism have an effect on in term of the drug level
extensive = low drug levels to produce therapeutic effect
poor = higher drug level and may result in increased risk of an adverse drug reaction
how does induction of enzymes lead to metabolism variability
induction may mean drug effect is reduced as more metabolism means faster clearance and there is less active drug to cause effect
how does inhibition of enzymes lead to metabolism variability
mean drug effect is decreased as less metabolism means slower clearance so more active drug to cause effect
what are the 2 types of inhibition of enzymes in metabolism
reversible when inhibitor is competitive
irreversible inhibition as metabolized by enzyme and then that metabolite irreversibly binds enzyme rendering it inactive
how does genetic variability lead to metabolism variability
polymorphism alter expression and activity
gene mutation result in altered proteins and altered phenotype
what are 4 non genetic reasons for metabolism variability
age/immaturity
sex
pregnancy
disease
how does age/immaturity affect metabolism variability
younger means there is reduced avail of endogenous cofactors needed for metabolism and enzyme systems arent fully developed
how does sex affect metabolism variability
differences in steroid hormones can affect the expressions of different drug metabolizing enzymes.
Sex influences weight and fat distribution and these physiological diff can affect pharmacokinetics
how does pregnancy affect metabolism variability
opposing changes in drug metabolism that can occur during pregnancy
some enzyme activities are increased in pregnancy
how does disease affect metabolism variability
liver disease and cardiac disease may limit blow flow to liver
Impact liver enzymes and perfusion that’s important for distributing drugs so limited blood flow to liver can impact extent and rate of drug metabolism
