1
Q
What does ADME stand for?
A
Absorption, Distribution, Metabolism, Elimination
2
Q
If the drug pKA > pH, the drug will be ___. If the drug pKA < pH, the drug will be ___
A
pKA > pH, drug will be protonated (basic)
pKA < pH, drug will be deprotonated (acidic)
3
Q
How is renal control of pH related to drug elimination?
A
- increasing the acidity of urine enhances excretion and decreases reabsorption
- drug gets protonated (ionized)
- prevents overdose and minimizes side effects
4
Q
volume of distribution
A
- the amount of drug found in the body compared to its concentration in the blood
- to what extent is the drug distributed from the blood to tissues
- V = (dose of drug)/([drug] in blood in mg/ml)
5
Q
What does a high/low volume of distribution indicate?
A
- high volume of distribution = higher [drug] in extravascular than in blood
- low volume of distribution = drug doesn’t leave vasculature
6
Q
What complications arise due to a high volume of distribution?
A
- widespread distribution = more side effects possible, decreased efficacy, requires more drug = more off target effects
7
Q
clearance
A
- the factor predicting rate of elimination
- related to [drug]
- CL = (rate of elimination)/([drug])
- additive: CLsystemic = CLliver + CLlungs + CLkidney + CLother
- CL per organ is rate of elimination based on [drug] that reaches the organ
8
Q
renal clearance
A
clearance of unchanged drug in the urine
9
Q
half-life
A
- time needed to decrease amount of drug in plasma by 50%
- t1/2 = 0.7V/CL
10
Q
What do higher half lives indicate?
A
- less elimination
- less drug required
- low volume of distribution (stays in vasculature longer)
- less rate of decay
11
Q
accumulation
A
build up of [drug] in the body when drug doses repeated, due to the previous dose not being cleared completely
12
Q
accumulation factor
A
= 1 / (fraction of drug lost in 1 interval)
13
Q
bioavailability
A
the fraction of unchanged drug that reaches the blood/systemic circulation after administration
14
Q
Cmax
A
max concentration of drug absorbed
15
Q
tmax
A
time at which max concentration of drug is absorbed (Cmax)
16
Q
AUC
A
- area under the curve
- represents total drug exposure over time
17
Q
system bioavailability (F) equation
A
F = f x (1–ER)
where f is extent of drug absorption and (1-ER) is oral bioavailability (ER is extraction ratio)
18
Q
first-pass effect
A
initial metabolism of drug by the liver
19
Q
extraction ratio (ER)
A
ER = (CLliver)/(Q)
where CLliver is clearance rate from liver and Q is hepatic blood flow (rate of blood flow through liver)
20
Q
If a drug is highly extracted by the liver, will it have a large or small “f” value?
A
small “f” value
- low absorption due to higher loss of drug
21
Q
Which of the following routes of administration do NOT incur the first-pass effect: oral, IV, IP (intraperitoneal), topical, sublingual, transdermal, rectal?
A
- IV
- topical
- sublingual (directly into systemic circulation)
- transdermal
- rectal (if lower since lower rectum drains into systemic circulation, 50% if upper)
22
Q
What does the time course of a drug depend on?
A
- dose of drug administered and absorbed
- EC50/ED50: drug needed to inhibit target
- half-life: plasma drug concentration over time
23
Q
immediate/fast effects
A
- drug target is within cardiovascular system or easily accessible from blood stream
- travel time minimized
- drug effect is directly related to drug concentration
- max effect almost immediately seen after administration
24
Q
delayed effects
A
- changes in [drug] in plasma result in changes drug effects
- time taken to distribute to tissues
- time taken for dissociation of drug from target/receptor
25
cumulative effects
- high potency; drug binds to target fast after absorption
- drug effect occurs after enough drug is bound to the target to induce some change (amount, location, function) in the target to induce clinical benefit
- cumulative exposure
26
xenobiotics
foreign molecules that enter the body
27
What is the main goal of drug metabolism?
- to enhance drug elimination
- decrease half life
- prevent toxic accumulation of drug in the body
28
How is metabolism related to the half life of a drug?
- slow metabolism = longer half life
| - fast metabolism = shorter half life
29
How do enzymes catalyze reactions?
increase the liklihood of reaction occurring by holding 2 molecules in close proximity to each other
30
catalysis
increases the rate of reaction by lowering the activation energy
31
phase I reactions
- enzymes add small polar groups
- makes drugs more polar and hydrophilic
- removes lipophilic groups
- example: oxidation
32
phase II reactions
- add big bulky groups to original drug or to the phase I product
- forms inactivated drug conjugates that can be easily excreted
- example: addition of glucose makes drug more hydrophilic
33
microsomes
- mini metabolic machines
| - isolated from smooth ER in cells to study phase I rxns
34
mixed function oxidases (MFOs)/monooxygenases
- a P450-mediated substrate oxidation mechanism
Step 1: Fe3+ state, P450 oxidized
Step 2: NADPH reducing agent donates electron to CYP450 with the help of P450 reductase, reducing Fe3+ to Fe2+
Step 3: second time NADPH donates electron, does not change Fe2+ but allows binding of O2 to CYP450
Step 4: drug is oxidized (attachment of -OH), CYP450 back to Fe3+ state
35
induction of P450 activity
- increase in drug metabolism over time
- increase rate of elimination
- increased risk of toxicity if drug metabolite is reactive
- example: cirrhosis due to ethanol-mediation induction of CYP2E1
36
inhibition of P450 activity
- decrease in drug metabolism over time
- binding to the heme iron (competitive inhibition/suicide inhibition)
- inability to metabolize leads to accumulation of other drugs
37
examples of P450-catalyzed oxidation reactions
- aromatic hydroxylations
| - aliphatic hydroxylations
38
other phase I transformations (not P450-catalyzed)
- amine oxidation
- dehydrogenations (increase polarity; RCH2OH –> RCHO)
- hydrolysis (of esters and amides)
39
metabolic enzymes other than P450
- esterase/lipase: ester bond hydrolysis into alcohol and acid
- peptidase/protease: peptide bond hydrolysis
- amylase: breakdown of sugar into glucose monomers
40
glucuronidation
- UGT enzyme transfers glucuronosyl onto nucleophilic atom
- donor: UDP-G
- substrates: alcohols, carboxylic acids, amines, amine oxides (N-OH)
- metabolites: glucuronides
41
sulfation
- sulfotransferase enzyme transfers sulfate group to nucleophilic atom
- donor: PAPS
- transfers sulfate onto hydroxyl (-OH) or amine (-NH2) of the substrate
- metabolite: sulfamates
42
GSH conjugation
- glutathione transferase transfers glutathione (GSH) group onto electrophile
- donor: GSH itself (a nucleophile)
- metabolite: GSH attached to electrophilic centre of drug
43
N-acetylation
- N-acetyltransferase (NAT) enzyme transfers acetyl group onto the N of an aromatic amine group
- deactivates drug activity
- donor: acetyl-CoA
- metabolite: acetylated aromatic amine
44
methylation
- methyltransferase (MT) enzyme transfers methyl group onto nucleophile
- donor: SAM
- transferred to alcohol, amine, etc.
- metabolite: + charged methylated nucleophile
45
Are phase II or phase I reactions faster?
- phase II rxns are faster
- reactive donor groups
- neutralizing rxns occur faster than oxidation/reduction
46
P-glycoproteins
associated with drug efflux
47
metabolism in the lungs
- very fast absorption and high bioavailability
| - lower levels of metabolism (less amount of enzymes)
48
metabolism in the gut
- gut wall epithelium with P-glycoproteins and CYP450 enzymes
- part of the first pass effect
- gut flora can also metabolize drugs
49
metabolism in the skin
- intercellular route: between cells
- transcellular route: passes through cell membranes and cytosol (*face higher metabolism through this route due to enzymes in cytosol)
50
metabolism in the brain
- CYP450 and some phase II enzymes
| - can create active metabolites (increase half life in CNS) or deactivate them
51
Explain how acetaminophen illustrates the idea that drugs can be transformed into reactive intermediates that are toxic to many organs.
- acetaminophen can undergo phase I oxidation, glucuronidation, sulfation, ultimate goal is GSH conjugation but intermediate is reactive and toxic
- if acetaminophen is taken in excess, the body doesn't have enough GSH + glucuronidation and sulfation pathways are already saturated
- reactive intermediate will begin to bind to proteins in the liver, covalently modifying them = liver cell death
- antidote: acetylcysteine binds to the intermediate, competing with proteins
52
prodrug
compound that is metabolized after administration into an active drug
53
promoiety
- a group originally attached to a drug to mask it
- removed by enzymes/chemical transformation
- should be safe and rapidly cleared, not active
- enhances solubility and delivery to site of action
54
2 goals of the prodrug approach
enhance absorption and active transport
55
Levodopa (L-DOPA) prodrug
- prodrug for morphine: treatment of parkinson's disease
- L-DOPA is a substrate of the LAT1 transporter in BBB endothelial cells but dopamine is not
- converted to dopamine in neurons
- enhanced active transport
- bioavailability improved if co-administered with carbidopa (decarboxylase inhibitor), as parcopa
56
Bacampacillin prodrug
- prodrug for ampicillin, an antibiotic that inhibits cell wall production
- increases absorption bc it is more hydrophobic and less prone to first-pass effect and metabolism
- slowly converted to ampicillin by esterases in gut intestinal wall and increases its absorption into blood
57
pharmacogenomics
the role of our genome in drug response
58
epigenetic modifications
covalent modifications to the genome due to environmental or biological changes
59
genetic polymorphisms
- changes in nucleotide or number of nucleotide repeats (SNPs and CNVs)
60
single nucleotide polymorphisms (SNPs)
- single nucleotide substitution, insertion or deletion
61
copy number variations (CNVs)
sections of the genome are repeated
62
organic anion transporter (OATPs)
- membrane molecule influx or efflux transporters
BIO200
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