3a. Metabolism - ADME II: elimination of drugs

Question 1

what is metabolism

Answer 1

biotransformation of drugs

enzyme mediated chemical change to the drug molecule, either building molecule up or breaking down

parent (unchanged) -> metabolites

Question 2

how does metabolism help drug elimination

Answer 2

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)

Question 3

many drugs are lipophilic to aid what and what does this means for elimination of parent form

Answer 3

lipophilic o aid absorption and distribution = high reabsorption in kidney and poor elimination in their parent form

Question 4

metabolism produces more ___ metabolites that are better/harder excreted from body

Answer 4

hydrophilic polar meetabolites

better excreted

Question 5

does metabolism abolish activity of drug

Answer 5

usually but not always

Question 6

what are the 3 things that drug metabolism can result in

Answer 6

promotion of activity
no change
toxic

Question 7

what is metabolism resulting in promotion of activity

Answer 7

drug metabolized to metabolites that are more pharmacologically active

Question 8

what is metabolism resulting in no change in activity

Answer 8

metabolite formed is equally biologically active as parent drug

Question 9

what are the 5 major sites of drug metabolism

Answer 9

liver
intestinal wall
GI tract
plasma
lungs

Question 10

why is the liver a possible site of drug metabolism

Answer 10

high levels of metabolising enzymes

Question 11

why is the intestinal wall a possible site of drug metabolism

Answer 11

CYP450 enzymes

Question 12

why is the GI tract a possible site of drug metabolism

Answer 12

gut bacteria and proteases

Question 13

why is the plasma a possible site of drug metabolism

Answer 13

esterases - prodrug activation

Question 14

why is the lungs a possible site of drug metabolism

Answer 14

metabolism of aerosol sprays

Question 15

what happens to drugs administered orally in the part of the organs

what effect does metabolism in the digestive organs have on bioavail

Answer 15

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

Question 16

what does first pass metabolism affect

Answer 16

affects the bio avail/fraction of dose that will reach systemic circulation

Question 17

can drugs adminstered in IV form still udnergo metabolism

Answer 17

cant occur with first pass metabolism but can undergo systemic metabolism

Question 18

first pass metabolism is before/after systemic circualtion

Answer 18

before

Question 19

systemic metabolism is before/after systemic circualtion

Answer 19

after

Question 20

what are the 4 types of metabolism reactions

Answer 20

oxidation
reduction
hydrolysis
conjugation

Question 21

what is an oxidation metabolism reaction

Answer 21

increase proportion of oxygen on the molecule

Question 22

what is an reduction metabolism reaction

Answer 22

loss of oxygen

Question 23

what is an hydrolysis metabolism reaction

Answer 23

water molecule is added to compound usually resulting in bond cleavage

Question 24

what are the 3 functionalization reactions for metabolism and what do they all do

Answer 24

create/modify a functional group

oxidation, reduction, hydrolysis

Question 25

what is conjugation metabolism reaction

Answer 25

addition of endogenous substrate

Question 26

what are the 4 types of conjugation metabolism reaction

Answer 26

glucuronidation sulphataion acetylation glutathionylation

Question 27

what does conjugation metabolism reactions do to the molecular mass, polarity and excretion

Answer 27

increase molecular mass polarity/water solubility increase increase likelihood of excretion

Question 28

what are the phase 1 reactions

Answer 28

oxidation, hydrolysis and reduction

Question 29

what is a phase 2 reaction

Answer 29

conjucation

Question 30

functionalisation reactions can result in metabolites that are more prone to what

Answer 30

more prone to undergo conjugation reaction

Question 31

what is the misconception about phase 1 and 2 reactions names

Answer 31

phase 1 isnt always before phase 2

Question 32

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?

Answer 32

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

Question 33

what is the most important functionalisation reaction

Answer 33

oxidation

Question 34

what is the enzyme that facilitates oxidation

Answer 34

CYP450

Question 35

what are the 3 families of CYP involved with drug metabolism and how many isoforms are responsible for majority of phase 1 reactions

Answer 35

CYP1,2, and 3 4 isoforms

Question 36

what 3 things does exidation require and which is the reducing agent

Answer 36

O2, NADPH (reducing agent), cytochrome p450

Question 37

what is the nomenclature of CYP family eg CYP3A4

Answer 37

``` C = cytochrome P = P450 wavelength 3 = family A = subfamily 4 = isoform ```

Question 38

what are conjugation reactions

Answer 38

synthetic reactions as it involves adding an endogenous molecule onto drug

Question 39

what is the endogenous molecule in a conjugation reaction normally

Answer 39

carbohydrate, an amino acid or something derived from the 2

Question 40

what does conjugation reactions do to the property of the molecule

Answer 40

makes it larger increase water solubility

Question 41

what is glucouronidation and what compounds is it common for

Answer 41

endogenous compounds and drugs

Question 42

what is the key enzyme for glucouronidation

Answer 42

UGTs

Question 43

what does UGTs do

Answer 43

transfer polar glucose derivative onto target molecule

Question 44

what is sulfonation carried out by

Answer 44

sulphotransferases

Question 45

what are major areas of high activity for sulphotransferases

Answer 45

SI, colon, liver, pancreas

Question 46

what does sulfonation do to the property of molecule and what is this good for

Answer 46

increases water solubility of molecule improves excretability in bile and urine

Question 47

what do sulphotransferase transfer

Answer 47

sulphonate from donor PAPs onto acetyl or hydroxyl group of receiving molecule

Question 48

what is a limitng factor for sulfonation

Answer 48

PAPS is synthesised in all almost all tissues but its depletion limits sulfonation

Question 49

for sulphotransferases what are forms associated with the cell membrane involved in

Answer 49

housekeeping

Question 50

what is glutathione conjugation done via

Answer 50

glutathione S transferases

Question 51

what does glutathione conjugation do

Answer 51

clean up system for reactive species generated in cells as well as other functions

Question 52

what does acetylation do to the properties of the compound and what does this achieve

Answer 52

generally decreases water solubility so that its more difficult to excrete metabolites in the urine

Question 53

what functions does acetylation have

Answer 53

housekeeper and homeostasis

Question 54

what does methylation do

Answer 54

adds lipophilic methly group to decrease water solubility

Question 55

what is methylation used for in terms of the types of compounds it facilitates

Answer 55

small endogenous compounds

Question 56

why are there variations seen in metabolism

Answer 56

drug dose required to achieve effective therapeutic blood levels can be diff in diff people metabolism rate in people genetic and non genetic factors

Question 57

what will extensive and poor metabolism have an effect on in term of the drug level

Answer 57

extensive = low drug levels to produce therapeutic effect poor = higher drug level and may result in increased risk of an adverse drug reaction

Question 58

how does induction of enzymes lead to metabolism variability

Answer 58

induction may mean drug effect is reduced as more metabolism means faster clearance and there is less active drug to cause effect

Question 59

how does inhibition of enzymes lead to metabolism variability

Answer 59

mean drug effect is decreased as less metabolism means slower clearance so more active drug to cause effect

Question 60

what are the 2 types of inhibition of enzymes in metabolism

Answer 60

reversible when inhibitor is competitive irreversible inhibition as metabolized by enzyme and then that metabolite irreversibly binds enzyme rendering it inactive

Question 61

how does genetic variability lead to metabolism variability

Answer 61

polymorphism alter expression and activity gene mutation result in altered proteins and altered phenotype

Question 62

what are 4 non genetic reasons for metabolism variability

Answer 62

age/immaturity sex pregnancy disease

Question 63

how does age/immaturity affect metabolism variability

Answer 63

younger means there is reduced avail of endogenous cofactors needed for metabolism and enzyme systems arent fully developed

Question 64

how does sex affect metabolism variability

Answer 64

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

Question 65

how does pregnancy affect metabolism variability

Answer 65

opposing changes in drug metabolism that can occur during pregnancy some enzyme activities are increased in pregnancy

Question 66

how does disease affect metabolism variability

Answer 66

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