Pharmacokinetics Flashcards
Oral administration of drugs
Must first pass through the gut epithelium
Absorption
A first-order process (i.e. the rate of is proportional to the amount of drug present at the site of absorption)
Cmax
Time at which absorption and elimination are equal to each other.
-max conc of the drug in the plasma
Tmax
The time where Cmax occurs
IV bolus
Maximal plasma concentration is instantaneous (Co)
What is oral bioavailability governed by?
Governed by solubility (GI lumen), permeability (GI epithelium), metabolism in the gut and liver
What is distribution from the plasma governed by?
Governed by membrane permeability, fenestration, blood flow. plasma protein binding and partitioning (into body fat)
Which organs have high fenestration? What does that mean?
- Liver and kidney
- Means that the drug can pass very easily
If a person is sick, what can that do to the degree of fenestration?
It can change
What has decreased blood flow?
adipose tissue, bone and synovia?
Why is it hard to treat a joint infection?
Because synovia has low blood flow, and it’s hard to get antibiotics into a tissue that’s not well perfused.
Fick’s Law (formula)
Flux (molecules per unit time) =
(C1-C2) x Area x Permeability/Thickness
Permeability (P)
proportional to lipophilicity/molecular weight
Most drugs are
weak acids or weak bases
Accumulation
Eventually plateaus because it is in equilibrium with elimination [Css—concentration steady-state]
Bioavailability
Used to indicate the fraction (F) of an administered dose of drug that reaches the systemic circulation unchanged.
What is the bioavailability of a drug administered via IV?
100%
Volume of distribution (Vd)
Relates the amount of drug in the body to the concentration of drug in the plasma
Small Vd occurs when?
Lipid solubility is low, plasma protein binding occurs and there is a low level of tissue binding
High Vd occurs when?
Lipid solubility is high, low plasma protein binding occurs and there is a high level of tissue binding
Rate of elimination of a drug
Is proportional to the amount of drug in the fluid characterized by the volume Vd
Rate of elim = k * A
units amt/time
Elimination Half-life, t1/2
The time when the original plasma concentration is 50% of initial dose.
Clearance (CL)
Is a factor that relates the rate of elimination of a drug to the concentration of the drug in plasma. Units are flow (such as 1 L/hr). vol/time
Dose/AUC
CL
Where is a drug that’s a weak acid be absorbed?
In the stomach
What does AUC tell us
total exposure to the drug
If we want to know how much of a drug is bioavailable, what do we look at on a graph?
AUC
(T/F) A drug distributes itself differently in different tissues?
T
What is lipophilicity expressed by?
n octanol/H2O
aka (nol-p)
What happens to permeability if we incr MW at the same nol-p?
less permeable
What happens to permeability if we increase nol-p at the same MW?
more permeable
An acid is uncharged when it is?
protonated
A base is uncharged when it is?
unprotonated
What happens after a weak acid is protonated and crosses a membrane?
It gets ion trapped based on the pH and establishes a new equilibrium and can’t diffuse back
Aspirin is strong acid, is more protonated in duodenum (pH 5) or plasma (pH 7.4)
in the duodenum (weaker base). Acid is more protonated in a more acidic environment.
this way it doesn’t want to be protonated to diffuse back into the duodenum
What is steady state?
- Accumulation and elimination are linear.
- People reach this after using a drug for a while.
- It’s a nice happy therapeutic range (Cp max and Cp min are consistent)
What does a graph look like for multiple dosing of an IV bolus?
There are spikes because you give a dose it clears, give a dose, clears….
Bioavailability eqn
F= [(AUC)oral / (AUC)iv] x [(Dose)iv / (Dose)oral]
Vd =
amount / Cp
Vd for bolus IV injection
- simplest case
- permits DIRECT calculation of initial conc of drug in plasma (Cp) for any given dose!
Elimination is almost always
“first-order”
What is a first order process?
rate of elimination of a drug is proportional to the amt of drug in the fluid characterized by Vd
How to calculate Cp
and what can we use this eqn for?
Cp = Cp(initial) x e^(-kt)
-use to calculate where along this slope on the graph (time vs plasma drug conc) you are from the initial dose (with known constant and known time)
First order rate constant (k)
-relates rate of elimination to the amount of drug
rate elimination = k * A
-uses reciprocal time units
Rate of elimination in terms of clearance (eqn)
rate of elimination = CL * C
Cp
plasma concentration
amount/vol
Why is clearance important?
- crucial for designing regimen for long term steady state drug administration.
- basically make sure to give you as much drug as you will clear so you’re at stead state level. if given too much will reach toxic level
Dosing rate =
dosing rate = rate of elimination = Cl * Css
CL derived eqns because CL is the key to other pharmacokinetic parameters.
CL= k*Vd
CL=Dose/AUC
CL practicalities
- CL is hypothetical volume of fluid that is effectively and completely cleared of drug per unit time
- The fluid containing the drug has apparent Vd
- CL can be total body or single extractions (like renal CL or hepatic CL)
Which clearance eqn is based on mass so doesn’t matter which model we use?
CL = Dose / AUC
Complication of 1 compartment model ex
Thiomental after IV bolus
- has different kinetics going to different places
- not used for maitenence because it builds up in fat so after a while it will come out of fat and person feels woozy. It is instead used to induce anesthesia bc goes to brain and viscera very quickly.
2 compartment model
- you’re not a well mixed 10 L sac, there is some slower step here as the drug gets out of the plasma
- a lot more mathematically complex
- makes the parameters we derived earlier more complex.
soft spots in drug development
spots in the chemical structure that human enzymes will immediately chew up so that (a) we will not keep delivering the way we think we are, and (b) we will not keep dosing the way we think we are.
Inactivating drug bio-transformation. What is it and what does it do?
Biotransformation can turn drug from active to inactive.
Inactivation of compounds- changes in structure lead to loss of receptor binding.
-It limits the duration of drug action
-Protection against toxic chemicals
Activating drug bio-transformation.
Biotransformation can turn drug from inactive to active
-For activation of pro-drugs – bc many drugs are not in their most active forms when we take them.
Excreting drug bio-transformation
- improves water solubility for easy excretion
- so increase hydrophilicity
- lower tissue distribution
- increase renal and bile excretion
- basically stick something on the drug that makes it more polar.
Toxic bio-transmormation
Bioactivation of cytotoxins, mutagens and carcinogens.
Ex- benzo(a)pyrene on it’s own is fine but once metabolized turns into nasty carcinogen
Most drugs can be metabolized by a single reaction (T/F)
False, multiple rxns
First pass effect
after you take a drug orally, it’s that first ride across your liver and lungs get metab before it hits systemic circ
Enterohepatic recycling. What is it, and for what type of drug will this happen to?
Drug goes from the liver into our bowels and then cycle back into liver and back to bowels.
-this will happen with drugs that aren’t polar enough (mildly lipophilic metabolite)
Phase 1 bio-transformations
- This is the “functionalization”
- First step of introducing a new functionality on the drug.
- Cyt p450 is the main one but there ARE others.
- oxidations
Synonyms for cytochrome p450
- monooxygenase
- mixed function oxygenase
How are cyps in animals, plants and bacteria
- membrane associated in animals and plants
- soluble in bacteria
Why is membrane association functionally useful?
Because we can do microsomal fractionation – can disrupt liver membranes and lower fraction be centrifuge, then we can use that fraction to perform metab on drugs and predict metab.
Explain how CYP 3A4 is classified
why is this classification good?
3 - gene family
A- subfamily
4- enzyme identity
-good because helps predict what their substrates will be and what their function will be
Catalysis of CYPs requires
-NADPH (high energy cofactor)
-molecular oxygen (O2)
energy intensive process so we need a living energy producing system to do this (you have to be breathing)
p450 catalytic cycle
- drug binds to cyp
- heme goes through reduction and oxidation– that is needed to bind to the drug to do it’s job
What does cyt p450 reductase do?
transfers electrons from NADPH to the P450s during catalysis
Typical cyt p450 reactions, what do most of them do?
- aliphatic hydroxylation (add OH to CH chain)
- S- N- oxidation (add O to S or N)
- O-dealkylation (remove alkyl)
- N-demethylation
- Oxidative deamination (remove amine)
- epoxidation (bad)- epoxide is unstable, reactive and binds to DNA
- they basically increase polarity
What kind of cyps to humans also contain?
which ones are important and which family is important?
58 CYP pseudogenes –these are not fully expressed. Only a small set are responsible for metab of drugs.
- Important 1A2 and 2E1
- 3A is important family
Because of low specificity, a single drug can metabolized by _____ p450s
also, a single cyp _____
several
-also a cyp can catalyze different reactions on the same drug
Indicibility of p450s and exs
- they are controlled by a large variety of TFs
-ex- 2E1 is induced by ethanol. If someone drinks a lot and then takes a tylenol, they will have a very different drug metabolism.
ex- cyp2B is induced by phenobarbital
Genetic variability of cyps
- show polymorphic expression
- cyps can be genetically variant across races and populations
- cyps vary by copy number – how many cyps expressed per gene. Higher copy number variants are fast metabolizers.
CYP34A
most abundant human cyp
What family are most of the liver cyps?
3A
What is CYP3A4 inhibited by
grapefruit juice and certain anti-fungals
CYP1A2
- impt in toxicology
- inducible by polycyclic aromatic hycrocarbons found in cigarette smoke
- inh by grapefruit juice
- substrates are caffeine
Phase II reactions
- conjugations – take the prod of phase I and add something to it.
- more likely to be inactive and MUCH more polar – allows them to get cleared.
- require also high energy cofactors (PAPS)
Glucuronic acid conjugation
- most significant phase 2 rxn
- co factor supply is readily available in liver
- variety of functional groups used as substrates can be conjugated
- glucuronic acid just replaces the hydrogen on the hydroxyl group (or amine, sulfhydryl)
UDP-glucuronosyltransferase (UGT)
- catalyzes glucaronic acid conjugation
- it’s microsomal
- present in liver but also in extra-hepatic tissue
- inducible but less impt bc phase 1 rxn is limiting factor. there are enough phase 2 enzymes to deal with all plase 1
Sulfation
conjugating group: SO3- (carrying charge so polar)
- the cofactor is more important and sometimes
- phase II rxn
- activated form of SO3- is PAPs
- saturable kinetics – the cofactor PAPs may be limiting
- certain drugs cant be adequately sulfated if you take them long time or take multiple drugs cleared by this mech
- significant for endogenous substrates (mostly steroids)– so high levels of certain drugs interfere with that pathway
sulfotransferases
enzyme for sulfation
- abbrev SULT
- has multiple families (10 enzymes in 3 families)
SULT1A1
- type of SULT for sulfation
- also works on estrogens
N-acetylation
- exception*- wemake the phase 2 metabolite less polar instead of more polar
- add acetyl group instead of taking it away
- Acetyl coA cofactor
N-acetylation typical reactions
- aromatic primary or aliphatic amines
- substituted hydrazine
- aryl-substituted sulfonamide
Integration of Phase 1 and phase II metabolism
- for a given drug you have demethylation or dealkylation, then hydroxylation then conjugation
- all of these happen at different ratios
- Most drugs are metabolized by more than one pathways
Factors affecting drug metabolism: age
- newborns don’t have many metabolic enzymes
- takeaway- be careful giving drugs to pregnant woman or newborn.
- elderly- metabolism slows, bp changes
Factors affecting drug metabolism: pathological and physiological states
-impairment of liver function really effects
Factors affecting drug metabolism: drug-drug interaction
- cyp induction
- many affect phase I enzymes
- one drug changes metab of another drug
- toxicity (comp inh of drugs metab by the same enzyme)
- unfortunate ex- seldane pro drug for allegra.
Factors affecting drug metabolism: genetic
- plolymorphism
- classified to EM (extensive metabolizers), (PM) poor metabolizers, ultrarapid metabolizers
Polymorphism in drug metabolizing enzymes and exs of polymorphic human enzymes
-not a random mutation, its a DNA seq difference in more than 1% of pop
exs- CYP2D6, CYP2c19, NAT, Aldehyde dehydrogenase
Determinants of pharmacokinetics
ADME; absorption, distribution, metabolism and excretion (elimination)
Drug metabolism can be
inactivation of active drugs; activation of pro-drugs; increases in water solubility for easy excretion; bio-activation of cytotoxins, carcinogens etc.
N-acetylation
Uses acetyl coenzyme A as a cofactor; products are less polar
