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291 Cards in this Set
- Front
- Back
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functional groups that are susceptible to hydrolysis
|
amide
ester |
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under what conditions does hydrolysis occur
|
acidic medium
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Fick's law describes what process
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simple diffusion
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passive diffusion
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no energy required
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2 "coefficients" associated with Fick's law
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diffusion coefficient (D)
permeability coefficient (Peff) |
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units of diffusion coefficient
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length^ 2/time
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units of permeability coefficient
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Length/time
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rate of diffusion is a variable
what is the letter associated with it |
v
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calculation of v (2)
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dn/dt
# molecules per unit time - (D A dC) / dx |
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letter corresponding to flux
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J
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calculation of J (3)
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v/A
-D dC/dx Peff dC |
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define permeability coefficient
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D/dx
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intestinal uptake means
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lumen to enterocyte
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intestinal efflux means
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enterocyte to lumen
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liver uptake means
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blood to hepatocyte
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liver efflux means (2)
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hepatocyte to blood
OR hepatocyte to bile |
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kidney uptake means
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blood to kidney cell
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kidney efflux means
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kidney cell to urine
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Pgp is a product of what gene
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MDR1
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facilitated diffusion
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carriers move something down its conc gradient
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transport through cells (vs. in between)
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through: transcellular
between: para |
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opposite of facilitated transport
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active transport
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facilitated vs. active transport
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facilitated = down conc gradient, no E required
active: against conc gradient, E required |
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primary active transport
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ATP directly used by the transporter
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secondary active transport
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uses electrochemical concentration gradient established by primary active transport
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buccal
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inner cheek
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pH of stomach
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1
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pH of small intestine
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6
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what is the layer of sugar chains hydrated with water in the small intestine called
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glycocalyx
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importance of the glycocalyx in drug absorption
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drugs have to penetrate this layer to be absorbed by the GI tract
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role of microbiota (bacteria) in drug absorption
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metabolize drugs
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fun factor that can change in the GI tract that affects drug absorption
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blood flow to the tract (ex. sympathetic and parasympathetic innervation)
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gastric empyting rate
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0.5-1.5h
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small intestine transit time
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1-3 h
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concept of residual length
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if a drug is completely absorbed before it gets all the way through the small intestine, it has a reserve (residual) length
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ASBT stands for
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apical sodium dependent bile acid transporter
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PEPT1 stands for
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oligopeptide transporter 1
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MCT1 (stands for)
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monocarboxylic acid transporter 1
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OATP stands for
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organic anion transporting polypeptide
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NPT stands for
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sodium dependent phosphate transporter
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what portion of the digestive tract does bile enter at
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duodenum
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what portion of the digestive tract does bile get reabsorbed
|
ileum
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name 3 bile acids
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taurocholate
ursodeoxycholic acid chenodeoxycholic acid |
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PEPT1 activity is ______ coupled
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proton
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implication of proton coupled nature of PEPT1
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affected by pH
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use of Acyclovir
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herpes
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absorptive = _____ for this grouping of transporters
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apical
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specific OATPs that are found in the intestine
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2B1
1A2 |
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which transporter is inhibited by grapefruit juice
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OATP1A2 and 2B1
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what inhibits OATPs
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grapefruit juice
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organ in which OATP1A2 and 2B1 are found
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intestine
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MCT1 stands for
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monocarboxylic acid transporter 1
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nucleosides vs. nucleotides
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Nucleoside = Sugar + Base
Nucleotide = Sugar + Base + Phosphate |
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indication for fosfomycin
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antibacterial
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indication for foscarnet
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antiviral
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indication gabapentin
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seizures
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indication baclofen
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spasticity
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indication of D-cycloserine
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antibiotic
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mrp2 stands for
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multidrug resistance-associated protein 2
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MDR1 stands for
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multidrug resistance protein 1
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BCRP stands for
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breast cancer resistance protein
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quality of pgp substrates (2)
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lipophilic
often anti-cancer |
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pgp transport characteristic
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ATP dependent
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measure of lipophilicity
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P and log P
partition coefficient |
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partition coefficient (log P) for optimal absorption (6 types)
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sublingual - 5.5
percutaneous - 2.6 CNS penetration 2 oral - 1.8 intestinal - 1.35 colonic - 1.32 |
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log P for 3 administration methods
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<0 injectable
0-3 oral 3-4 transdermal |
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log P that leads to toxic build up in fatty tissues
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4-7+
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druglikeness
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a measure of how druglike a substance is
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Christopher Lipinski's Rule of 5
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MW < 500
log P < 5 hydrogen bonding < 5 HB donors (NH or OH) < 5 HB acceptor (N or O with free electrons) <10 |
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what is an HB donor
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NH or OH
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what is an HB acceptor
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N or O with free electron pair
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lead-likeness
|
lipophilicity and MW are often increased to improve the affinity and selectivity of a drug candidate during drug discovery
But after hit and lead optimization, we want drugs to be drug-like. There are different rules for lead-likeness: MW <350-400 LogP < 4 solubility or scope for polar functions |
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CNS-likeness
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MW < 450
LogP < 3 HBD <4 HBA <8 |
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5 predictors of Drug absorption
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good water-lipid solubility
not very ionized stable in acidic medium substrate for transporters not a substrate for efflux transporters/metabolism |
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For a pair of acidic and basic drugs with similar lipophilicity compare their ionization lipophilicity
|
pH 1 - stomach
acid is mostly unionized WA absorbed more in stomach pH 6 - intestine acid = more ionized base = less ionized WB absorbed more in intestine overall: WB more "lipophilic" |
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although acids are less ionized in the stomach than in the intestine, more is absorbed in the intestine - why?
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intestine has greater surface area
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measure of rate of absorption
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tmax - smaller = faster rate
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measure of extent of absorption
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AUC (t to infinity)
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factors that decrease GI motility (9)
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food
anticholinergics narcotics acids surgery viscosity ulcers hypothyroidism exercise |
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why exercise decreases GI motility
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takes blood flow from the intestine
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name 2 anticholinergics
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atropine
propantheline |
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what kind of drug is meperidine
|
narcotic
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5 factors that increase GI motility
|
metoclopramide
alkali stress liquids hyperthyroidism |
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Methotrexate relies on the folic acid transporter in the intestine. How does morphine cause an interaction?
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rate of absorption is slowed (= higher tmax)
AUC increased - saturation of transporters is prevented |
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how metoclopramide affects ethanol absorption (ethanol is normally well absorbed)
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metoclopramide increases GI motility
t max decreased (rate increased) ethanol has high reserve length so AUC unchaged |
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how does propantheline affect ethanol absorption
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decreases GI motility
tmax increased (rate slowed) ethanol has high reserve length so AUC unchaged |
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3 possible rate limiting steps for absorption
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1. unstirred water level
2. membrane 3. blood flow |
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absorption rate limiting step for very lipophilic drugs
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unstirred water level
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absorption rate limiting step for very water soluble drugs and drugs absorbed via transporters
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membrane
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absorption RLS for drugs with good water and lipid solubility
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blood flow
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blood flow is the RLS for
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drugs with good water and lipid solubility
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membrane is the RLS for
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very water soluble drugs and drugs absorbed via transporters
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unstirred water layer is the RLS for
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very lipophilic drugs
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go back to slide 69
|
ok
|
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review the antitutorial slide 6 and 8
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ok
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order 8 organs from most to least blood flow rater per 100g tissue
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rapidly perfused
adrenal glands kidneys liver heart brain poorly perfused skin muscle fat |
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7 example drugs in order from most to least plasma protein bound
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warfarin
diazepam tolbutamide phenobarbital salicylate acetaminophen ethanol/antipyrine/lithium |
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example of drug that is 99% bound
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warfarin
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example of 3 drugs that are 100% unbound
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ethanol/pyrine/lithium
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protein binding can be stereoselective
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+ and -
R and S |
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4 reasons protein binding is important
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only unbound drug can have activity, toxicity, etc.
fluctuation in drug conc within therapeutic range explain stereoselective disposition of drugs drug-drug interactions |
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the CSH barrier is at the _____
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choroid plexus
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what intercellular structure is responsible for barriers (ex. BBB)
|
tight junction
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factors that increase drug distribution
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decreased ionization
lipophilicity stability in blood more transport in than transport out more tissue protein binding than plasma protein binding |
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2 vessels that supply the liver
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portal vein
hepatic artery |
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fun fact about liver secreting bile
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excretion of bile salts creates an osmotic gradient that gives rise to bile flow
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at what point do bile salts enter the intestine
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duodenum
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bile salts enter at the duodenum, emulsify fat and are returned to the liver
what is this process called |
enterohepatic circulation
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sinusoid
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blood vessels in the liver
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2 membranes of liver cells
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1. sinusoidal membrane
2. canalicular membrane |
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what is a canaliculus
|
tube that transports bile
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NTCP stands for
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sodium dependent taurocholate cotransporting peptide
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MW has to be less than ____ for glomerular filtration
|
5000
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GFR (normal)
|
110-140 ml/min
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6 characteristics of an ideal marker for GFR
|
filtered freely
100% unbound biologically inert not secreted not reabsorbed easily measured in plasma and urine |
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2 common endogenous GFR markers
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blood urea nitrogen (BUN)
creatinine |
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why creatinine is not perfect GFR marker
|
secreted a bit
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the secretion of creatinine results in over/underestimation of GFR
|
over
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normal creatinine clearance
|
125-140ml/min
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creatinine clearance in moderate renal insufficieny
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20-50ml/min
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creatinine clearance in severe renal insufficieny
|
<10ml/min
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best exogenous GFR marker
|
inulin
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what is tubular secretion
|
movement of organic ions from the blood, through the kidney cell
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what kind of substances undergo tubular secretion
|
organic ions
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how OAT1,3 work
|
dicarboxylic acid exchanger
tertiary transport NaK ATPase creates an Na gradient The Na gradient is used to cotransport: Na in (down conc gradient, alpha ketoglutarate in - up its conc) then OAT uses the alpha ketoglutarate gradient to transport OA in and alpha ketoglutarate out - down its conc gradient) |
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inhibitor of OAT1,3
|
probenecid
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3 enzymes found in the kidney
|
3A4
UGT SULT |
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ascorbic acid transporter is dependent on ____
|
Na
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inorganic sulfate ion is dependent on ___
|
Na
|
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passive reabsorption depends on
|
lipophilicity
charged? pH of urine and pKa urine flow rate |
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example of a diuretic
|
furosemide
|
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what do diuretics do
|
dilute urine
increase flow rate |
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how and why CL of WB and WA change with change in urinary pH
|
WB: NH2 --> NH3+
As pH increases, base is less likely to be charged (more conjugate acid when pH is low) Less charged = more passive reabsorption = less excretion Therefore: pH increase = clearance decrease WA: HA --> A- more acid when pH low so more charged when pH increases more charged = less reabsorption so higher pH = higher excretion |
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effect of lipophilicity on kidney clearance
|
more lipophilic = more reabsorption = less cleared
|
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probenecid and penicillin interaction
|
probenecid keeps penicillin from being excreted in urine
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basolateral/apical
|
basolateral = blood
|
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which points you should choose for the 2 point method when doing calculations with C(t)=C0e-kt
|
last point
other point should be in the elimination phase |
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when going back in time - what is the equation and what do the variables mean
|
C2=C1e^+Kt
C1 is the present conc C2 is the past conc use positive time |
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assumptions of the 1 compartment model
|
1. instantaneous, homogeneous distribution
2. system is linear - twice the dose = twice the conc |
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when a system might not be linear
|
saturation of transporters, enzymes, protein binding
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average person has ___ litres of body water
|
40-50
|
|
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average person has __L of blood
|
5
|
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how to calculate mass balance
|
if you know actual volumes (ex. of water and oil)
calculate the mass from the c and v |
|
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higher lipophilicity = (higher or lower) Vd
|
higher
|
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Vd
|
volume of sampled fluid needed to account for the concentration found
a proportionality constant |
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3 uses for Vd
|
1. tells how much dose is needed to achieve a particular concentration
2. in a general way, tells us where the drug is stored in the body 3. important for determining loading dose |
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why Vd can't be determined from an oral curve
|
can't back-extrapolate to C0
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minimum of Vd
|
5L
blood volume |
|
|
why basic drugs tend to have higher Vd than acids
|
bases sequester in membranes because the + charge interacts with - charged phospholipids
also get trapped in acid organelles such as lysosomes |
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factors that determine a drugs Vd
|
physicochemical properties: MW, charge, transporters , acid/base, lipophilicity
protein binding |
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how MW affects Vd
|
high MW = confined to plasma
|
|
|
Vd of ions
|
rapidly distribute through ECF but do not easily cross cell membranes
unless there are transporters (ex. K) |
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how acid/base affects Vd
|
bases have higher Vd
bases sequester in membranes because the + charge interacts with - charged phospholipids also get trapped in acid organelles such as lysosomes |
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what is used to measure plasma volume
|
indocyanine green
|
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|
barriers to distribution
|
GI tract
vascular walls cellular walls |
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% of whole blood volume that is plasma
|
55%
|
|
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whole blood vs. serum vs. plasma
|
plasma: blood + anticoagulant - cells
serum: blood - cells - clotting factors |
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% of whole blood volume that is cells
|
45
|
|
|
% of whole blood that is cells NAME
|
hematocrit
|
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|
hematocrit
|
% of whole blood that is cells
|
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what is assumed about protein binding equilibrium
|
free concentration is equal in all tissues
|
|
|
which is more important - tissue or blood protein binding
|
tissue because tissue mass exceeds blood volume.
so blood protein binding has to be way higher to win the tug of war |
|
|
example of drug that is highly blood protein bound but has little tissue protein binding
|
warfarin
|
|
|
Vd equation
|
Vd = Vb + Vt (fub/fut)
Vb: blood volume vt: body water (30-50L) fub: fraction unbound in blood fut: fraction unbound in tissue |
|
|
assumption associated with the Vd equation
|
drug can distribute to all areas of body water - not necessarily true due to BBB, etc.
|
|
|
how does elimination affect Vd
|
it does not
ratio of dose to concentration does not change |
|
|
male body weight
|
50 kg + 2.3kg/in over 5ft
|
|
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female body weight
|
45.5kg + 2.3kg/inch over 5 ft
|
|
|
blood volume is __ % of IBW
|
8
|
|
|
body water is __ % of IBW
|
60
|
|
|
Vd varies among (2)
|
drugs
patients |
|
|
when do you use actual BW and when do you use IBW
|
IBW used if patient is fat or normal
adipose has low water content If underweight, their body water will be less than ideal |
|
|
which fluid do you assume is being sampled
|
plasma
|
|
|
clearance definition
|
irreversible removal of drug from the body
|
|
|
what is the most important PK parameter
|
CL
|
|
|
why CL is so important
|
determines maintenance dose and dosing schedule
|
|
|
importance of Vd vs. CL in determining drug dose
|
Vd - loading dose
CL - maintenance dose |
|
|
% Cardiac output that liver and kidney each get
|
25
|
|
|
liver has 2 blood supplies
|
portal vein
hepatic artery |
|
|
definition of PK
|
study of how drugs move around the body and how quickly this occurs
|
|
|
PK clinical studies that are often regulatory requirements for drug approval
|
1. first in man
2. SAD 3. MAD 4. relative bioavailability (fasted vs. fed, disease vs. healthy, etc.) 5. bioequivalence (required for generic drug product approval) |
|
|
bioequivalence primarily refers to
|
bioavailability
|
|
|
single ascending dose
|
group of patients given small dose and observed
Then a different group of patients is given a higher dose and observed |
|
|
multiple ascending dose
|
same as SAD but the group gets multiple doses at a given level
|
|
|
Studying drugs before and after PK theory was developed
|
Before: could only look at dosing regimen and relate it to desired and adverse effects. after: can look at dosing regimen, how it impacts exposure in the body, and desired and adverse effects
|
|
|
Is PK needed for drugs with wide therapeutic indices
|
Not as much, can just start with standard dose, and then see what happens
|
|
|
therapeutic triangle
|
top = therapeutics
this branches into PK and PD PK relates dose to conc PD relates conc to effect |
|
|
preclinical - test population
|
lab studies
animals |
|
|
phase I - test population
|
healthy volunteers
|
|
|
phase 2 - test population
|
patients
|
|
|
phase 3 - test population
|
patients
|
|
|
purpose of preclinical (2)
|
safety
biological activity |
|
|
purpose of phase 1 (3)
|
safety
dose PK |
|
|
purpose of phase 2 (5)
|
proof of concept
dose ranging safety in special populations PK in special populations risk factors |
|
|
purpose of phase 3 (2)
|
placebo control
multicentre |
|
|
which phase is post market
|
phase 4
|
|
|
how many years of testing vs. how long patents last
|
12 years of testing
patents last 20 years |
|
|
Not as much, can just start with standard dose, and then see what happens
|
phenytoin
|
|
|
Drug effect depends on ____ more than plasma conc
|
conc in site of action
|
|
|
3 categories of things that can contribute to the pharmacologic effect (4 in each category)
|
1. Dosage form
2. Frequency 3. Route 4. dose 2. Drug related 1. Conc-effect relationship 2. Site of effect 3. Disposition of drug 4. Potency of drug 3. Patient related 1. Environmental exposure 2. Genetic constitution 3. Organ function 4. Enzyme activity |
|
|
Sites of drug sampling (6)
|
Plasma
Blood Serum Urine Milk saliva |
|
|
What do you look at next if there is not sufficient drug in the blood/plasma/serum
|
Plasma
Blood Serum Urine Milk saliva |
|
|
plasma vs. serum
|
plasma: anticoagulant added
|
|
|
name 2 clotting factors
|
fibrinogen
fibrin |
|
|
Comparison of plasma and serum drug concs
|
usually identical
|
|
|
Comparison of plasma/serum and whole blood drug conc
|
May be very different
|
|
|
Extravascular
|
everywhere other than systemic circulation
|
|
|
intravascular
|
systemic circulation
|
|
|
disposition
|
PK synonym
|
|
|
bioavailability definition
|
extent to which a drug reaches bloodstream compared to IV admin
|
|
|
IV admin AKA
|
systemic admin
|
|
|
systemic admin means
|
IV
|
|
|
parenteral admin
|
any rate of admin other than through the digestive tract
especially injection |
|
|
liberation (LADME)
|
how quickly and where does the drug get released from its formulation
|
|
|
distribution answers 3 qs
|
where does the drug go
how fast does it get there how long does it stay |
|
|
MTC
|
minimal toxic conc
|
|
|
MEC
|
minimal effective conc
|
|
|
what is k in this equation
dC/dt=-kC |
elimination rate constant
fraction of total volume cleared of drug per unit time smaller k = slower elimination |
|
|
why is k negative in this equation (First order elimination)
dC/dt=-kC |
because dC/dt is negative - the conc is decreasing over time
|
|
|
look at slide 42-44 lec 1
|
ok
|
|
|
assumptions of the 1 compartment linear model
|
1. one compartment
2. rapid mixing 3. linear |
|
|
assumptions of the 1 compartment linear model
1 compartment assumption |
drug conc in tissues is proportional to drug conc in blood
|
|
|
assumptions of the 1 compartment linear model
rapid mixing |
drug is mixed instantaneously in blood
|
|
|
assumptions of the 1 compartment linear model
linear model |
drug elimination follows first order kinetics
double the dose, double the conc |
|
|
units of diffusion coefficient (D)
|
Length^2/time
|
|
|
units of permeability coefficient (Peff)
|
Length/time
|
|
|
units of flux (J)
|
moles/(time x area)
mol . m^-2 . sec |
|
|
which of the 2 parameters (AUC or tmax) is affected in the same way by slowed gastric emptying for most types of drugs
|
tmax - increased
rate decreased because most absorption takes place in the intestine |
|
|
effect of slowed gastric emptying on acid labile drugs
|
in stomach longer
more destroyed by acid decreased AUC |
|
|
effect of slowed gastric emptying on poorly soluble drugs
|
drug gets more time to dissolve
AUC increases |
|
|
effect of slowed gastric emptying on drugs taht are substrates of transporters
|
AUC increases
drug level is kept below saturation of transporters |
|
|
effect of slowed gastric empyting time on drugs that have good water and lipid solubility
|
they have long residual length
so absorption is unchanged - good whether gastric emptying is fast or slow |
|
|
absorption RLS for very water soluble drugs
|
membrane
|
|
|
bloodflow is the RLS for
|
drugs with good water and lipid solubility
|
|
|
For WBs, high pKa means
|
stronger base
|
|
|
for WAs, high pKa means
|
weaker acid
|
|
|
name three drugs that are highly unbound to plasma protein
|
ethanol/antipyrine/lithium
|
|
|
bile acid production pathway
|
cholesterol ->
chenodeoxycholic acid -> cholic acid -> taurocholic acid |
|
|
source of bile acids
|
cholesterol metabolism
|
|
|
source of bilrubin
|
heme metabolism
|
|
|
bilirubin
|
heme ->
bilirubin -> bilirubin monoglucuronide -> bilirubin diglucuronide |
|
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name of blood vessels in liver
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sinusoids
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2 assumptions in compartment model that seem similar and why they are different
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1 compartment: drug in the blood is in rapid equil'm with drug in the tissues. Drug conc in tissues is proportional to drug conc in blood at all times
rapid mixing: drug is mixed instantaneously in blood or plasma |
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PK reasons that drugs fail (8)
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1. poor solubility (can't make good formulations
2. poor absorption 3. extensive first pass metabolism 4. High CL 5. non-linear kinetics 6. enzyme inhibition/induction 7. active metabolites (=variability in response) 8. polymorphic metabolism |
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transport across membranes depends on 8 qualities
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lipophilicity
charge size polar surface area stability nature of membrane nature of medium on either size presence of transporters |
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effect of charge on membrane transport (whether it is positive or negative, not charged or uncharged)
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negative = slower because
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for 2 membrane types, charge doesn't matter for molecules small than 5000 (MW)
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blood capillaries (except testes, placenta, CNS)
renal glomerulus |
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which is more porous nasal mucosa or GI
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nasal
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why amino acids are so polar
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zwitterion
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order the following from most to least polar
urea hydroxyl ester carbonyl ether amino acid amide |
MOST POLAR
amino acid urea amide hydroxyl ester carbonyl ether LEAST POLAR |
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Lineweaver-Burke plot is ___ vs. ___
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y axis: 1/v
x axis: 1/[S] |
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Eadie-Hofstee plot is __ vs. __
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y axis: v
x axis: v/[S] |
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Hanes-Woolf plot is __ vs. __
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y axis: [S]/v
x axis: [S] |
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Lineweaver Burke x-int
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-1/Km
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Eadie-Hofstee: x-int
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vmax/km
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Hanes-Woolf: x-int
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-Km
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which is the best (Lineweaver-Burke, EAdie Hofstee, or Hanes Woolf) and why
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Hanes-Woolf because error is similar for high and low substrate conc. When [S] is very low, there is lots of error when it is the denominator
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what is the symbol for the substrate concentration at half max velocity under conditions of inhibition
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Klm
(L is superscript, m is subscript) |
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what happens to vmax under competitive inhibition
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unchanged
when [S] is higher, they win the contest in [I] vs. [S] |
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what happens to Km when there is competitive inhibition
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increases - affinity decreases
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Ki =
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[E][I]/
[S] |
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what happens to Lineweaver-Burke plot - competitive inhibition
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1/vmax vs. 1/[S]
xint = -1/Km b: 1/vmax m: Km/Vmax b = same (vmax doesn't change) m increases because Km increases x int gets closer to 0 because Km increases |
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fun fact about noncompetitive inhibitors
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they can bind to E alone or ES
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effect of non competitive inhibition on vmax
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inhibitors take enzyme out of action even when they are bound to substrate, even if you increase [S], the enzyme will not work
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how do noncompetitive inhibitors affect Km
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unchanged
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effect of noncompetitive inhibition on lineweaver-burke plot
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1/vmax vs. 1/[S]
xint = -1/Km b: 1/vmax m: Km/Vmax b = increases because vmax decreases m increases because vmax decreases x int stays the same because Km is unchanged |
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definition of CL
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volume of blood cleared of drug per unit time
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CL cannot exceed
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volume of blood delivered to clearance organ per unit time
(flow rate to that organ) |
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fu AKA
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fp
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what does Fe mean
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fractional excretion
ratio of renal CL to filtration CL |
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implication of FE = 1
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fractional excretion
ratio of renal CL to filtration CL = 1 net filtered |
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implication of FE > 1
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net secreted
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implication of FE < 1
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net reabsorbed
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how to calculate k without half life
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slope of ln conc vs t
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units of AUC
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mass x time
volume ex. gh/L |
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substrates of methylation
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R-XH (X=O,N,S)
need 2 OH groups but you only methylate one of them |
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substrates of glutathione conjugation
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R-X (X=O,N,S)
the glutathione replaces the x |
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substrates of amino acid conjugation
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R-COOH
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name for k from IV bolus lecture
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elimination rate constant
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uetrect magic number
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0.1%
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bsep stands for
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bile salt export protein
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mate stands for
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multidrug and toxic compound extrusion
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ntcp stands for
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sodium dependent tauocholate cotransporting polypeptide
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substrates of glucuronidation
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phenols
alcohols COOH N hydroxy |
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substrates of sulfation
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phenols
alcohols NO COOH |
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substrates of acetylation
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aromatic amines
hydrazines hydroxylamine rarely aliphatic amines |
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draw a hydrazine and a hydroxylamine
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ok
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substrates of methylation
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R-XH (X=O,N,S)
need 2 OHs but methylate one |
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substrates of glutathione conjugation
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RX (R=O,N,S)
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transporters that require Na (7)
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NT
NTCP NPT ascorbic acid inorganic sulfate ion ASBT OCTN1N2 |
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2 transporters that require proton
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MCT
PEPT |
