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40 Cards in this Set

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  • Back
typically, drug metabolism ___ the pharmacologic activity of drug
decreases
drug metabolism facilitates drug excretion two ways
more water soluble
more easily recognizable by things like p glycoprotein transporter
clopidogrel is an example of
a prodrug that has to be activated by metabolizing enzymes (CYP450)
codeine is an example of
a prodrug that has to be metabolized to morphine
what is an example of something being digested by CYP450 making it into a carcinogen?

thank you, may I have another example of toxic substance being made?
aflatoxin B1 which gets turned into an electrophile that goes after DNA

acetaminophen also is oxidized to an electrophile that binds proteins and causes liver toxicity
most drug metabolism happens in

stuff also happens in
the liver

kidney, intestine, lungs,

but technically everywhere even skin and prostate
___ CYP450's play and important role in drug response. An example being
extrahepatic

skin CYP450 and dermatitis when allergies to certain chemicals. Sometimes an initial mechanistic step is metabolism of the chemical to form a protein adduct or "hapten"
what's the basic CYP450 rxn?

what phase is this?
NADPH + H + RH + O2 --> ROH + H2O + NADP

phase I
cytochrome P450's are expressed on the ___

they contain ___. Are in close proximity to __ which does what?
ER

heme. NADPHP450 oxidoreductase which puts electron from NADPH to the Fe on the CYP450
Phase II what 4 groups did we learn
glucuronide
sulfate
GSH
N-acetylation
what's involved in glucuronidation?
most predominant
uses UDP-glucuronsyltransferases
children suck at this so can OD on stuff.

Usually decreases activity but morphine is a notable exception
what's involved in sulfation?
cofactor PAPS is conjugated to the drug
what's involved in GSH conjugation?

where do you see high levels of this activity? what is the clinical implication?
GST GSH S transferase catalyze GSH onto reactive electrophiles which helps prevent damage

In drug resistance to chemotherapeutic agents, so inhibiting the GST's helps make drugs work better --> can be targeted by using prodrugs like TLK286
What is GSH?
gamma glutamate, cysteine and glycine.

If it runs out there's more oxidative damage to liver and other things
How does n-acetylation work?
n acetyltransferases NAT metabolize with aromatic amine or hydrazine
What variations happen with n-acetylation?
SNP of NAT impact pt response to treatment: Isoniazid for TB is metabolized by NAT. Slower acetylators have bad NAT and consequently higher plasma concentration and increased risk of isoniazid induced toxicity
acetaminophen is an example of
a drug metabolized by both 1 and 2 phases since Phase I makes it toxic electrophile and Phase II does GST to non-toxic form
If you are overdose and need more GSH you get
N-acetylcysteine
What is the one that metabolized the majority of administered drugs?
CYP3A
drug transporters do lots of stuff in absorption excretion homeostasis uptake influx. they're mediated by two superfamilies
solute carriers
ATP binding cassette transporters
what is up with solute carriers?
generally uptake transporters that use secondary and tertiary active transport
what about ABC transporters
on extra and intracellular membranes. Function as efflux pumps to remove chemicals from area usually active transport
impact of transport on drug action x4
in liver, transport into hepatocytes and excretion in bile

oral bioavailability: into enterocytes, active excretion into intestinal lumen

renal clearance: transport into proximal tubular cells and excretion into tubular lumen

BBB: restricts drug entry to CNS
P-glycoprotein: describe location, job, organs
lumenally expressed efflux transporter: lots in GI, liver, brain and kidney.

pumps stuff out to limit cellular exposure, oral absorption, CNS exposure. for kidney and liver it expels stuff out to excrete.

tumors use this because it's awesome protective
what's the story with statins and some enzymes
Statins lower lipids and have low bioavailability (5-30). CYP3A4 and OAT1B1 operate on it. CYP3a4 can get inhibited which means less metabolism. OAT1B1 can be inhibited which means less liver uptake. These make it toxic -> myopathy.
Which CYP has to do with if you're a poor, intermediate, ultrarapid, or extensive metabolizer?
CYP2D6
CYP2D6 metabolizes all sorts of stuff including
tamoxifen: a hormone-dependent breast cancer drug. Goes to endoxifen. unclear if poor metabolizers should still take this.
What drug did get a warning for CYP poor people?
clopidogrel for poor CYP2C19 metabolizers- affects platelet aggregation
mercaptopurine treats
it's metabolized by
if you have bad copies of it what happens?
MP treats leukemia
TPMT
get myelosuppression and greater risk for secondary cancers. You have excessive MP concentrations -> their doses need to be lower.
who has decreased drug metabolism?
less than 1 month, older than 65 (multiple drugs, poor renal function, decreased hepatic flow)
which gender has more adverse drug reactions?
why?
example drug
females
both pharmacodynamic and pharmacokinetic reasons- differences in CYP3A and UGT and P glycoprotein

torasemide is diuretic but women (estrogen related) weren't metabolizing with CYP and had higher blood conc of torasemide
liver diseases affect drug metabolism because
CYP's activity decreases with liver decrease- CYP2C19 is sensitive. Glucuronidation situation can be altered, so you need to test people's livers to make sure you're on good dose
what are ways drugs can interact?
alter metabolism like inducing or inhibiting CYP3A expression, competing for binding site (grapefruit juice on CYP3A)
what induces CYP3A4?
Rifampin or St. John's wort at receptor PXR. That means cyclosporine will be metabolized faster
what was the case study with drug interactions and codeine?
CYP3A4 neutralizes codeine and CYP2D6 changes codeine to morphine. If it's put in with CYP3A4 inhibitors in a person who has ultrarapid CYP2D6, the pt can OD on morphine
so which drugs were inhibitors
CYP3A4 substrate cyclosporine being inhibited by ketoconazole and grapefruit juice
which drugs were inducers
st john wort and rifampin
what was acetaminophen story?
phase I CYP and phase II GST act on it. GSH can run out and you can add n-acetylcysteine to get more GSH

alcohol ruined this.
which drugs were prodrugs
codeine CYP2D6
clopidrogrel
What did CYP2D6 affect?
codeine and tamoxifen