Module 1: Toxicokinetics (ADMMET)

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1
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what is toxiokinetic?
what the body does to a chemical

* study of mvmt of cmpd w/in the body ie ADME
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concentration time curves

* determine administration route
knowt flashcard image
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what is toxicodynamics?
what the chemical does to the body

* study of pharm/tox actions of a cmpd
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first order kinetics

* linear
first order kinetics

* linear
* constant fraction of drug is eliminated/time (1/4 each time)
* amount eliminated is proportional to amount in body
* elimination is NOT saturated
* most drugs eliminated this way
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zero order kinetics

* non-linear
zero order kinetics

* non-linear
* constant amount of drug is eliminated/time (8 mg)
* rate is not proportional to concentration or dose
* w/inc dose → saturation occurs
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kinetic models
* empirical models: if limited info
* compartmental models
* groups all tissues into 1 or more compartments
* well stirred
* based on linear assumptions using linear differential eqns
* physiological based pharmacokinetic model: based on known anatomic/phsyio
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1 compartment model
1 compartment model
* instantaneous distribution = all tissues behave the same
* one slope
* 1 compartment of blood & highly perfused tissues → drug well represented is hydrophilic
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2 compartment model
2 compartment model
* central & peripheral compartment (poorly perfused tissues ie fat)
* 2 slopes = 2 compartments
* drug well-represented is small, non-ionized
* plasma > peripheral tissue distribution
* \
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3 compartment model
3 compartment model
* bone & adipose tissue
* perfusion limited
* slow to accumulate/slow to release → not clinically significant but can be more toxicity
* 3 slopes = 3 compartments
* plasma > peripheral tissue > deep compartment distribution
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Cmax & Tmax
max measured concentration & time of max concentration
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Area under the Curve (AUC)
measure of total systemic exposure (how much actually got into circulation from dose)
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bioavailability (F)
fraction of cmpd reaching systemic circulation intact

\
F = AUCext/AUCiv \* Doseiv/Doseext
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poor oral bioavailability reasons
* poor drug absorption from GIT
* cmpd is ionized at all pH of GIT
* binds to food
* unstable at stomach pH
* gut microflora metabolize
* cmpd by metabolic enzymes
* Pgp efflux
* cmpd doesn’t dissolve
* poor blood flow at site of administration
* hepatic 1st pass metabolism
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volume of distribution
apparent vol w/in which a drug is distributed in the body

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Vd = dose/C0 = mg drug/Cp (recall dec w/PPB inc)

C0= y-intercept
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total body clearance (CL)
* vol of blood completely cleared of drug
* indicates rate at which cmpd is removed from plasma

\
CL = dose/AUC
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elimination half life (t1/2)
time for plasma conc to decline by 1/2

* time course of drug elimination → done is \~5 half-lives
* time course of drug accumulation

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t1/2 = 0.693/Kel = (0.693\*Vd)/CL
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multiple exposures & steady state
multiple exposures → leftovers → accumulations → input=output → depends solely on elimination t1/2

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steady-state = 4-5 elimination t1/2
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factors that can alter kinetics
* age
* chemical interactions: PPB, metabolism
* disease
* pharmacogenomics
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elimination

* metabolism
* excretion
removal of a cmpd from plasma → dec in conc

* cmpd is chemically transformed into metabolites
* process by which a cmpd is eliminated from body w/o a chemical change
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routes of elimination

* renal
* non-renal?
* feces (bile, 2nd most common way)
* sweat
* lungs
* saliva
* milk
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kidney fxn
* cleansing of blood
* regulation & maintenance of fluid/chemical balance
* production of urine to remove waste
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nephron flow of filtration
nephron flow of filtration
blood enters from renal arteries into afferent arterioles → glomerulus capillaries → in efferent arterioles which surround tubules → bowman’s capsule (filtering) → PCT → LOH → DCT → CD → reabsorption into peritubular capillaries
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total renal elimination = ?

* flow of glomerular filtration? secretion? reabsorption?
filtration rate + secretion - reabsorption = ?

* glomerular filtration = blood from afferent arteriole to lumen of tubules
* secretion = blood from peritubular capillaries to lumen
* reabsorption = tubular lumen to blood from peritubular capillaries
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glomerular filtration

* substance MW that are freely filtered?
* drive by ?
* GFR?
* \~25% CO reaches glomerulus
* MW < 5,000 are freely filtered
* > 70,000 are not
* GFR = vol of plasma filtered by kidneys/min
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if a molecule is bound to albumin it won’t filter through glomerulus, why?
serum albumin MW = 69,000
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active tubular secretion
* mvmt from blood to tubular fluid
* active transport process
* ionized drug
* not usually affected by PPB
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how does addition of Probenecid to Penicillin prolong therapeutic effect?
active tubular secretion is slowed bc Probenecid and Penicillin are competing for the same transporter → Abx is cleared slower
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passive tubular reabsorption

* depends on ?
* effect of charged/uncharged?
* conc gradient
* urine flow
* lipid solubility (Kow)
* urine pH & ionization
* drugs
* pathophysio
* diet
* carnivores (pH 5.5-7)
* herbivores (7.5-10.5)
* uncharged → chance for reabsorption
* charged/ionized → stays in tubules to excretion
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urinary pH & excretion of drugs - ion trapping
recall if pKa < pH → more H+ in soln → molecule is ionized → more likely to be eliminated
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renal clearance & lipophilicity & ionization
* inc lipophilicity → dec renal CL
* → inc passive reabsorption
* → inc PPB
* uncharged → dec renal CL
* → inc passive reabsorption
* charged → trapped in urine
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t/f: cmpds which are weak acids are excreted faster when the urinary pH is more alkaline as compared to acidic.
true
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factors affecting renal CL
* urine pH, pKa of drug
* urine flow rate
* physiochemical properties of drug
* blood flow to kidneys
* disease states
* drug interactions
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renal clearance (CLr)
rate at which plasma is cleared of cmpd by kidney

filtration only: CL = Fu\*GFRplasma

active secretion > reabsorption: CL > Fu\*GFRplasma

reabsorption>active secretion: CL > Fu\*GFRplasma
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t/f: the most rapidly eliminated cmpds are those w/high GFR & that are actively secreted but aren’t passively reabsorbed.
true
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fecal elimination/excretion
* direct elimination of non-absorbed cmpds
* efflux pumps
* via bile
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bile
* made in liver/stored in gallbladder
* functions
* facilitate intestinal absorption of ingested lipids
* major route for cholesterol elimination
* elimination route drugs
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biliary elimination of drugs
* predominantly cmpds w/high polarity/some lipophilicity
* MW >325; >500 most favorable)
* glucoronide or GST conjugates
* active transporter: drug-drug interactions (DDI)
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enterohepatic recycling
from liver/gallbladder → common bile duct → small intestine → hepatic portal vein → liver

* exists to recycle bile


* may prolong drug t1/2
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what processes does phase 2 metabolism include? what is the purpose?
* sulfation\*\*
* glucoronidation\*\*
* glutathione conjugation ****
* acetylation
* amino acid conjugation
* methylation

\
inc hydrophilicity & tagging
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t/f: phase II conjugation enzymes are ‘faster’ than phase I CYPs.
true, so Phase I is generally the rate limiting step of elimination
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phase II conjugation rxns occurs mainly in which organelles? which main organ?
* cytosol, S & R ER
* liver, but also skin, intestine, brain, spleen, nasal mucosa
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Glucoronidation

* enzyme
* what is being added? from what cofactor?
* purpose
Glucoronidation

* enzyme
* what is being added? from what cofactor?
* purpose
* UDP-glucornosyltransferases (UGTs)
* glucuronic acid from uridine-diP (UDP) gluconic acid to lipophilic drug
* the sugar acid moiety of glucuronides makes cmpd more polar + water-soluble
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liver microsome assay
for any new drug → mix w/liver microsomes & do mass spec → can ID metabolites to see which transferases involved
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UGT families and substrates

* nomenclature
UGT1A1 (UGT + family + sub-family + isoform)

\
UGT1A8 = androgens, morphine

UGT1A9 = ibuprofen, estradiol

UGT2B7 = NSAIDs, morphine
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morphine

* skips what phase?
* what specfic enzyme?
* _ gluconoridation → 2 products, which one has analgesic potency?
* skips phase I → glucoronidated directly
* UGT2B7
* regioselective → morphine-6-glucornide has higher analgesic/pain relieving potency (made only 10% of time
* but 90% of time: morphine-3-glucoronide → no analgesic effect
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sulfotransferases (SULT)

* transfer what group? from what cofactor?
* phase I substrates?
* purpose
* sulfonate group from phosphoadenosine-phosphosulfates (PAPS)
* R-OH, -NH2, NH-OH, phenols
* makes cmpd more polar + water-soluble
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SULT nomenclature
SULT + family + sub-family + isoform (same as UGT)
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how does safrole (from Sassafras tree) become a carcinogenic metabolilte?

1. P450-mediated hydroxylation
2. SULT-mediated conversion to sulfate ester (unstable)
3. ester decomposes to (allyl) carbonium ion → reactive E+ → binding to G in DNA → liver carcinogen
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SULT vs UGT

* how does their activity vary at high or low concentrations of drug?
SULT vs UGT

* how does their activity vary at high or low concentrations of drug?
* SULT are low capacity, but high affinity → work better at low doses
* UGT are high capacity, but low affinity → work better at high doses (SUGAR RUSH)
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Glutathione-S-Transferase (GST)

* structure of cofactor GSH (glutathione), where is it mostly located?
* pKa depression
* GSH is tripeptide, most abundant antioxidant in cells


* GST conjugates Nu- GSH cofactor to E+ cmpds
* pKa depression = allows GST-bound GSH to act as a Nu- at a physiological pH
* thiol group pKa = 9.5 → pKa 6 → Nu- activity at pH 7.4 (deprotonated S-)
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GST nomenclature
GST + sub-family + isoform

3 main families

* cytosolic, mitochondrial, microsomal
* cytosolic have 11 subfamilies
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GSH conjugation of acetominophen (Tylenol)
* phase I metabolite, NAPQI → conjugated w/GSH → excreted
* if acetaminophen is OD’d → GST saturation → depletes GSH in liver → fatal liver toxicity (3-4days)
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where does biotransformation occur?

* in body?
* in cell?
* liver = richest source for phase I & II
* primarily in S&R ER (microsomes)
* also in cytoplasm, mitochondria, lysosomes, nuclei
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a fat-soluble toxins → phase I via cytochrome P450 enzymes (CYPs) which include:

* how?
* oxidation
* reduction
* hydrolysis
* hydration
* dehalogenation

\
goal = conversion of hydrophobic drugs → more water-soluble via

* expose/introduce functional groups ie -OH, NH2, SH, COOH
* to inc hydrophilicity & polarity
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CYP nomenclature

* how many human CYPs?
CYP + family + subfamily + isoform

* each CYP isoform comes from a different gene
* \
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what are the 6 CYPs that account for 86% of drug biotransformation?
* CYP1A2
* CYP2B6
* CYP2C9
* CYP2C19
* CYP2D6
* CYP3A4/5
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what are CYP polymorphisms?
minor nucleotide sequence changes → affects dose & toxicity of drug
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2 types of drug interactions w/CYPs
* inhibition
* competitive binding
* enzyme saturation
* induction
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alicyclic oxidation
alicyclic oxidation
epoxide + H2O → diol

via epoxide hydrolase (or reverse: epoxygenase)

* present in all tissues

\
=> inc hydrophilicity
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aliphatic oxidation

* ibuprofen ex
w-1 oxidation (2nd to last CH3) via CYP2C9 → alcohol metabolite

or

w-oxidation (last CH3) via CYP2C8 → carboxylic acid metabolite

\
both non-toxic & easily eliminated
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aliphatic oxidation

* valproic acid
valproic acid

w oxidation (CYP2C19)

* 2-n-propylglutaric acid (non-toxic)

\
w-1 oxidation (CYP2C9)

* 4-Hydroxyvalproic acid (4-HPA) → inhibits mitochondrial fatty acid oxidation → hepatotoxic/mitotoxic
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alkene epoxidation

* carbamazepine + valproic acid DDI
carbamazepine →

carbamazepine-10,11-epoxide (forms adducts w/DNA & proteins) via epoxide hydrolase →

trans-10,11-dihydroxy carbamazepine (diol)

\
\*\*DDI: valproic acid inhibits epoxide hydrolases → inc carbamazepine-10,11-epoxide

\
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polycyclic aromatic hydroxylation

1. procarcinogen & PAH benzo\[a\]pyrene (BaP) oxidized to **epoxide**
2. BaP epoxide gets hydrolyzed to **diol**
3. BaP diol gets further oxidized to the __**carcinogen BaP diol epoxide (BPDE)**__

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BPDE is resistant to hydrolysis by epoxide hydrolase → forms DNA adducts
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what are the 4 properties of chemicals that dictate its site of storage/toxic action?
* Kow
* pKa/pKb
* Vd
* PPB
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Kow

* correlation w/bioconcentration factor
Kow = octanol/water partition coefficient

* at equilibrium → if Kow if high → high lipophilicity

\
* positive correlation of logBCF and logKow
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BCF & Kow relationship
BCF & Kow relationship
* hydrophilic cmpds show (-) logKow & low BCF

\
* logKow 1-7 → linear relationship w/BCF
* logKow > 7 → can precipitate

\
* why are there outliers? transporters!
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pH and pKa
the smaller pKa, the stronger the acid

\
* if pKa > pH → low pH, high \[H+\] → cmpd is protonated
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which one will cross plasma membrane faster? which one will accumulate in fat over longer period of time?
* PCB by high logKow and not ionizable
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volume of distribution (Vd)

* PPB effect on Vd
* Vd = vol in which current amount of drug in body must be dispersed to give current Cp; indicates if drug tends to stay in plasma or go to other tissues
* Vd = mg drug in body/ mg/L drug in plasma


* high Vd = cmpd goes to extravascular compartments → higher dose req’d
* low Vd = cmpd tends to remain in plasma → lower dose req’d

\
* if PPB → low Vd bc cmpd stays in plasma
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Vd: hydrophobic drug in fat vs skinny dog
fat dog has larger Vd bc has more fat for drug to sequester into and out of plasma → requires larger dose
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how does warfarin have a high Cp but a low Kow?
PPB
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effect of PPB bound to drug
ex) HSA = human serum albumin which interacts w/most drugs

cannot

* cross cell membranes
* interact w/receptor to produce effect
* be metabolized
* be excreted
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absorption/administration routes
enteral

* oral, sublingual/buccal, rectal

\
parenteral

* IV, IM, SC, ID, IA, IP, IT

\
topical

* transdermal, inhalation, intranasal, intraocular, intravaginal
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parenteral injection routes
directly into systemic circulation

* IM: slower absorption than IP but steady


* SC: bypasses epidermal barrier, slow
* IV: direct into circulation

\
intraperitoneal (IP, into peritoneal/abdominal cavity)

* GI tract, gall bladder, pancreas, spleen
* quick absorption bc high vascularization
* primarily absorbed into portal circulation (liver) & systemic circulation → cmpd needs metabolic activation in liver
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t/f: if toxicant undergoes 1st pass metabolism, it will be often less toxic if administered orally than IV.
true, but does not apply for toxicants w/selective organ toxicity or bioactivated in liver
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rank toxicity of absorption routes
IV > inhalation > IM/SC > dermal > IP > oral

only IP & oral are metabolized by liver/GI first
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cardiovascular system of ingestion vs inhalation
ingestion


1. stomach
2. intestine
3. liver
4. R-heart
5. R-lung

\
inhalation


1. L-heart


1. body tissue
2. brain
2. R-heart
3. R-lung
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t/f: toxicant cannot produce systemic injury until absorbed.
false only if toxicant doesn’t have caustic/burning properties
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where are most digested fats, proteins, drugs absorbed?
small intestines
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mode transport for

* weak acids/bases
* hydrophilic substances
* hydrophobic substances
weak a/b → simple diffusion (in non-ionic form)

\
hydrophilic → facilitated diffusion via pores/channels

* if very → active SLC transport

\
hydrophobic → simple diffusion

* very → absorbed into lymphatics (lacteals) via chylomicrons
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lymphatics system
stomach → intestines → AVOID LIVER, lymphatic system → R-heart → lungs → L-heart → body tissue
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polar vs non-polar elimination
polar

* to liver via portal vein → excreted into bile w/o entering systemic circulation

\
non-polar

* CM → skip liver → selective toxicity
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chemosensitization to combat MDR
process where non-toxic cmpd sensitizes a cell toward uptake/effect of another cytotoxic cmpd

* ‘distracts’ drug export pump via competitive or allosteric binding → allows drug uptake into cell
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competitive dye uptake assay

1. calcein-AM is non-fluorescent, cell permeable (transporter substrate)
2. intracellular esterase cleave AM → calcein
3. calcein is fluorescent, membrane-impermeable → accumulates (can’t use transporter)

\
* if a drug interacts w/transporter → blocks CAM export → bright cell
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transport proteins abundance
solute carriers (SLCs) > channels > active transporters
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types of active transporters
* ATP binding cassette type (ABC)
* secondary active - solute carrier (SLC)
* most euk ABC-transporters are efflux transporters
* most euk SLC are uptake transporters
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ABC vs SLC: which is in all kingdoms of life?
ABC-type
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human ABC transporter superfamily
ABCB, ABCC, ABCG
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ABC transporter nomenclature
ABC (family) + subfamily + member + isoform
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types of multi-drug resistance (MDR) ABC transporters
* chemotherapy
* AbR
* insecticide resistnance
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which ABC are brother in arms?
ABCB1 + ABCG2 = 1st line of defense in concert w/CYPs → work to reduce drug bioavailability
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drug design to combat MDR
* inhibitors
* downregulation
* non-recognition
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molecular methods to combat MDR
RNAi

* prevent transcription of transporter protein

\
CRISPR/Cas9

* knock out gene that encode transporter
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toxic agents

* chemical
* physical
* biological
* industrial chemicals, food additives, drugs, gases
* dust, abestos, radiation, nanoparticles
* bacterial, fungal, plant, animals
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toxic agent terms
* toxicants = synthetic, man-made
* toxins = biological in nature
* venoms = injected by bite or sting
* poisons = touch, ingestion
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persistent organic pollutants (POPs)
natural chemical elements or pharmaceuticals
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types of assessments

* exposure
* concentration
* dose
* exposure = extent of human contact
* concentration = level or amount of substance
* dose = specified quantity of a substance administered
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dose/concentration curve
knowt flashcard image
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potency metrics
ED50 = median effective dose in 50% of population

TD50 = median toxic dose “ “

LD50 = median lethal dose “ “
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therapeutic index (TI)
therapeutic index (TI)
range of blood levels wherein a substance is producing the desired effect w/o toxicity

\
TI = TD50/ED50 (toxic dose/effective dose)

\
low TI → more toxic → need to be given more frequently at lower doses (microdosing)

high TI → less toxic