Drug metabolism Flashcards
Processes that prevent continuous drug action
elimination/excreation
metabolism
Drug metabolites are usually more ________ then the drug ingested thus easliy excreated
poloar
most drugs enter the body _______ thus are difficult to excrete
lipophilic
In most cases metabolism will take active drug–>
inactive metabolite
A drug that is converted to active form by drug metabolizing enZ
prodrug
a prodrug is inactive until
metabolized
the more drugs we take the more at risk we are for
adverse affects
Drugs withdrawn from the market often d/t this reason
drug-drug interactions d/t drug metabolism
These guys do oxidation, reduction, dealkylation or hydrolysis
Phase I enZ
This enZ will often introdue or reaveal a functional group
Phase I enZ
Phase I enZ actions
oxidation, reduction, dealkylation or hyrolysis and introduce or reveal a functional group
These guys have conjugation of durg or durg metaboliet to endogenous substrate molecule
Phase II enZ
responsible for : Drug + conjugant–> Drug-conjugant
Phase II enZ
CYPs are examples of
Phase I enx
CYPs will often
make lipophilic drugs more soluble in water
These guys add large, polar conjugates to make drug super water soluble
phase II
Common location for drug metabolizing agents
portals of entry/exit
liver (HIGHEST)
GI, kidneys, lungs
Subcellularly where are the Phase I enZ located ?
In the SER microsomes
Subcellularly, where are phase II enZ located?
most are cytosilc
What venous system will take drugs to liver from the GI system
portal venous sytem
What drug administration is exposed to 1st pass effect
orally administered
Significant drug metabolism can occur before reaching general circulation d/t
first pass in intestines and liver
Drugs exposed to 1st pass will need _____ dose
higher
bioavialibty will ______ d/t first pass
lower F
F for IV administration
1 or 100%
What are two reasons for poor F
poor absorption or large first pass effect
Morphines’s F d/t first pass
.33
If i gave IV dose of 10 mg of morphine to relieve pain, what oral dose would i need to match that?
30 mg
Two key Phase I enZ
Cytochrome P450s = CYPs
Flavin-containing monooxygenases
Cytochrome P450s and Flavin-containing monooxygenases are examples of:
Phase I enZ
P450’s are anchored to:
outer face of ER
Core of P450’s
Fe
P450’s conjugate what to our substrates (drug)
O2 and we get S-OH +H20
P450 reductase use what to get the 2e- to add to our substrate?
NADPH –> NADP + 2e-
molecular ration of P450s per P450 reductase
10-20 P450s: 1 P450reductase
CYP stands for
cytochrome
CYP2B10: 2 stands for
gene family
CYP2B10: B stands for
Gene subfamliy
CYP2B10: 10 stands for
isoform
Human P450’s has _____ families
18
3 P450’s involved in drug metabolism
CYP1, CYP2, CYP3
There are _____ human P450 genes
with _____ of them involved in drug metabolism
57
15
Inidivudual differences in _____ result in big difference of catyltic activity and drub metabolism
isofrm
This CYP handles 50% of drug metabolism
CYP3A
CYP3A handles____ % drug metabolism
50
This cyp handles 25% drug metabolism
CYP2D6: DEPRESSENTS
This CYP handles 19% drug metabolizm
CYP2C19: includes warfarin, phenytoin
Relative CYP isoform content does/does not equate to significance in role of drug metabolism
does not
CYP 2D6 responsible for metabolism of _____%
and has ______% expression
25% drugs
1.5% is expressed
FMO stands for
flavin-containig monooxygenase
What are the substrates for flavin monooxygenase (FMO)
soft nucleophiles like N, SP or Se
Does FMO react with endogenous soft nuecleophiles?
nope, just interacts with exogenous soft Nu’s
what are expamples of endogenous soft nucelophiles
glutathione or cysteine
FMO’s have broader or more specific substarte profile then P450’s
broader
What type of products do Flavin-containing monooxygenases procude?
more polar and less toxic then CYPs
What results in broad substrate range for FMO’s?
it’s hydorperoxyflavin intermediates
What FMO is expressed in liver, brain and kidney?
FMO3
FMO3 makes up 2-3% of protein in
kidney
key FMO in liver
FMO3
Glucuronidation, sulfination and Acetylation are exapmles of
phase II enZ
UDP-glucoronic acid is example of
phase II enZ that does glucuronidation
PAPS is used in
sulfination; a phase II enZ
Acetyl Co-A involved in what?
acetylation in phase II enZ
Gluthathione conjucation is type of
phase II enZ
EnZ responsible for glucuronidation?
UDP-glucuronosyl transferase (UGT)
EnZ responsible for acetylation
N-acetyltransferase (NAT)
EnZ responsible for sulfination
Slufotransferases (SULT)
EnZ responsible for Glutathione conjucation
Glutathione S- transfereases (GST)
(NAT) stands for
N-acetyltransferase
(SULT) stands for
Sulfotransferases
(GST) stands for
Glutathione S- transfereases
(UGT) stands for
UDP-glucuronosyl transferase
IG, Phase II enZ makes metabolites more:
polar and less toxic
NAT does what to metabolites
makes some more polar, others less polar but makes most less toxic
Phase II enZ resposible for metabolism of almost half drugs
UGTs
bilirubin is metabolized by which phse II enz
UGT’s
What affects the Vmax of the Phase II enZ?
amount of conjugant available
Glucuronidation has _____ conjugant capacity and ______ amt of raw materials for conjugation
High conjugation capacity
High amt of materials available
Sulfonation has ______ conjugation capacity and ______ abundance of raw materials for conjucation available
Low conjucation capacity
low abundance of raw materials
Gutathione conjucation has ______ conjucation capacity and _____ abundance of raw materials for conjucation
low conjucgation capacity low materials (humans have high GSH initially, but gets rapidly depleated)
Two most common types of drug metabolism interactions:
EnZ induction
EnZ inhibition
Exposure to certain drugs/enviro chemicals will upregulate durg metabolizing enZ amount and or activity via transcription increase:
EnZ Induction
end result of enZ induction
more enZ d/t increased transcription = faster metabolism
Ethanol is an inducer of:
CYP2E1
Are Phase II enZ suseptible to enZ induction?
yes, UGTs and GST’s are induced by stuff like tobaccoo smoke, PAH or benzoapyrene
A single inducer can affect _____ drugs handled by that enZ
many drugs
EnZ indcuction increases
drug metabolism
Induction has what sort of affect on drug effects
can increase or decrease them
–depends on if metabolite is inactive or active
How long does induction take?
1-2 days
Are inducers quantally equal?
no
Inducers of specific isoforms (CYP isoforms) are substrates (T/F)
F: they may or may not be substrates
T/F: all substartes are inducers
fales, NOT all substrates are inducers
Some inducers are substartes (T/F)
true
Inhibitors of drug metabolizing enZ will inhibit enZ activity, but not:
gene expression
Drug inhibitors include:
competitive and non-competitive
3 types of P450 Inhibitors
Competitive substrates
Bind CYP heme–distrupts catalytic activity (non-competitive)
Suicide inhibitors (irreversible and non-competitive)
Major cauase of CYP releated drug interactions are due to:
competitive substrates
By binding CYP heme, these P450 inhibitors will:
distrupt catalytic activity (non-competitive)
How long does enZ inhibition take
immediate effect
How much does inhibition affect drug metabolism
highly variabel: depends on enZ and inhibitor and could be small or large effect
Serveral CYP2D6 inhibitors will reduce it’s activity to:
nearly zero
Grapefruit juice will _______ drug absorption
INCREASE
Grapefruit juice inhibits this intestinal CYP
CYP3A
By inhibiting CYP3A, grapeftruit juice will
increase net amount abosorbed to general circulation
the responsible ingrediant in grapefruit that inhibits intestinal CYP3A
furanocourmarin
Grapefruit juice is a big no for this CYP that handles 50% of drug metabolizm
CYP3A
FMO’s are _______induced or inhibited by clinically used drugs
NOT significantly
These guys are less suseptible to competitive subtrate inhibition than P450’s
FMOs
Whats the benefit to drugs that are handled by FMO’s
less potential for metabolic drug-drug interactions
other factors that affect drug metabolism
age, genetics, disease states, gender
most common cause of acute hepatic failure in US
acetaminophen use
Second most common cause of liver fail requiring transplant
acetaminophen use
First line Phase II’s that breakdown Acetaminiophen
SULT and UGT
What CYP will act on acetaminophen
CYP2E1
What will induce action of CYP2E1
ethenol
Product of acetaminophen–> CYP2E1 is
toxic and needs to be broken down by GST
