Week 3 Part 1 Flashcards
What are ideal drug like properties?
- Potency and selectivity vs. Target
- Dissolution and permeation through the GI tract
- Metabolic stability - good oral bioavailability and duration of action
- Absence/non-impact of dose/time dependent pk effects
- Able to be co-prescribed without complicated dosage adjustments
Cimetidine
First selective H2 Antagonist
Good compound - it worked
It had potent selectivity vs target
Oral drug - dissolution of permeation through the GIT
It has metabolic stability
Good oral bioavailability and duration of action
High dose significant risk of drug dose interaction
What is very important in pharmacokinetics?
Duration of action
What is ideal for a drug?
Short acting drug with anaesthetics properties
What do people vary in?
- Appearance and philosophy
- Physiology and biochemistry
- Occupations and habits
- Genetics - genotype vs phenotype
What does source of variability start of with?
- Compliance and comprehension
Give an example of source of variability
- Drug in tablet
- Drug in tablet in gut
- Drug in gut
- Drug in blood
- Drug in tissues
- Drug at receptor
What is source of variability
- Compliance/comprehension
- Release
- Absorption
- Distribution
What is a desired response?
Drug at receptor
Therapy
What does ADME stand for?
- Absorption
- Distribution
- Metabolism
- Elimination
What is Absorption?
All processes from the site of administration to the site of measurement
What is Distribution?
The reversible transfer of drug between the site of measurement and other sites within the body
What is metabolism?
The irreversible loss of drug from the body by biochemical conversion
Elimination
The irreversible loss of drug from the site of measurement within the body
What is excretion?
The irreversible loss of drug from the body
What is disposition
Elimination (clearance) + distribution
What is the ADME process?
Take drug orally
Absorbed across the gut wall
The gut is efficient with metabolism and drug transporters
It then hits the liver
What are the ADME questions?
- Is the drug absorbed by mouth?
- Which organs are exposed to the drug?
- How long does the drug stay in the body?
- How is the drug removed from the body?
- What factors influence drug handling?
- What is the appropriate route of administration?
- How should the drug be formulated?
- What are the appropriate doses and dose regimens?
- Which drug interactions are likely to be important?
How is the drug removed from the body?
Unchanged
Metabolites
What factors influence drug handling?
Physiological
Pathological
Pharmaceutical
Pharmacological
What are the appropriate doses and dose regimens?
- Animal studies (pharmacology and toxicology)
2. Patients
What is pharmacokinetics?
Forcing function behind pharmacodynamics
Seeks to provide a mathematical basis for the description of the time course of drugs (and their metabolites) in the body
Refers to the quantitiative study of the process of ADME
What is the purpose of pharmacokinetic (PK)?
Get a handle on where you think your therapeutic index/ window is
Maximum tolerated conc (MTC) vs a minimum effective conc (MEC)
What are the pharmacokinetic terms?
C-Max —> max conc
T-Max —> time at which max conc occurs
Half life (mean residence time (MRT)) - how often of the dosing regimen
Clearance and absorption - what happens between site of administration and blood sample
What are the key driving parameters behind half life?
- Volume of distribution
- Clearance
- Bioavailability
Why is clearance important pharmacokinetic parameter?
Defines how much of the dose that you have to give initially and how long does that dose stay in the body
What is bioavailability?
Study of the factors which influence and determine the amount of intact drug which gets from the site of administration to the site of action/measurement and the rate at which it gets there
What is absolute bioavailability?
A measure of the proportion of intact drug reaching the systemic circulation following extravascular administration compared with an intravenous dose
Cannot be > 1 (non-linear)
Low F = large variability
Absolute bioavailability
Ratio between what I take by mouth vs what’s the area of the curve following direct administration into the vein since all the drugs has done into the vein
The lower the oral bioavailability
The higher the variability
What is the benefit of a lower bioavailability drug?
We try to screen out the compounds earlier on in the drug discovery
What is the calculation for absolute bioavailability?
The ratio under the area of the curve following oral administration divided by area under curve following intravenous administration corrected for the doses
What is clearance?
Proportionality factor linking drug concentration in the blood (or plasma) to the rate of drug elimination
Flow parameter constant throughout the time interval
Intravenous administration
Distribute instantaneously in the whole of the body
All of the drug is distributed to the rest of the body before reaching the liver
Oral dose/administration
Has to go through the liver first
You get extraction/clearance across the liver
All of the drug must first pass through the liver before it reaches the rest of body
What is drug clearance?
The measurement of the volume of blood/plasma from which a substance is irreversibly removed per unit time
I.e. the rate of drug removal
What is rate constant?
Constant fraction per unit time
For hepatic clearance, you have an extraction rate across the liver, what is it?
Blood flow x difference in arterial and venous
What can the extraction ratio vary between?
0 - where no drug is eliminated
1 - where all the drug is eliminated in the liver
If you want a drug with good oral
Bioavailability
You want a low extraction ratio
What can extraction also be?
Metabolism
What do most oral drugs have?
Low extraction ratio
What is the equation for extraction ratio?
Rate of extraction/ Rate of presentation
Drugs with E > 0.7
High extraction ratio
Drugs < 0.3
Low extraction ratio
What does clearance relate to?
Product of organ blood flow to the extraction ratio
Represents the volume of blood that is irreversibly cleared per unit time
Renal clearance
Drug comes out the urine
CLt = (F.Dose)/AUC
F = intravenous always 1
What do people working in the drug discovery always look at?
The relationship of clearance to liver blood flow
What is the cause of low oBA and low clearance?
It doesn’t have permeation across GIT
Use of 70/30 rule
High > 70% of reference
Low < 30% of reference
Moderate 30-70%
The amount of the drug in the tissue
Function of the volume of tissue
Concentration of the tissue
Partition co-efficient
What is available for distribution?
Small molecules bind to proteins
Inbound concentration is available for distribution
Amount of drug in the tissue
VT . CT . Kip
VT = volume of tissue CT = tissue concentration KP = tissue:blood partition coefficient (CT/CV)
What key site do you look for in toxicology?
Adrenals
Small amount of tissue which has a very High blood flow rate
The lower the perfusion
The larger the tissue
The poorer tissue distribution
What is distribution dependent on?
- Affinity of drug for tissue (kp)
- Blood flow to the tissue
- Tissue size
What is volume of distribution?
relates to the amount of drug in the body at any one time to the amount at the measured site (blood/plasma)
Effectively a dilution factor
Initial distribution volume (Vd)
Volume of the space that the drug equilibrates with instantaneously
Volume of distribution based on terminal half life (Vdb)
volume of space associated with terminal phase
What is steady-state volume of distribution (Vss)
Volume of space that the drug occupies at steady-state
What is hypothetical value of volume of distribution?
- Totally body water = 42 L/70kg man
- Extracellular fluid = 20% body weight
- Plasma volume = 3 L/70kg man
- Blood volume = 5L/70kg man
What does the volume of distribution not tell?
Where the drug is
But it tells you where it isn’t
What is terminal half life?
Time taken for the drug concentration to decline to half its original value
Whatever drug you take
It will never disappear
There will always be a tiny amount
Clearance, volume and half life
Cl = K x V
If you want to increase half life
Reduce the clearance
What can some drugs bind to?
Plasma proteins
Can be species specific
Reversible and rapid process
- can be associated with idiosyncratic toxicity
What is drug-protein complex?
Large
Only unbound is available for distribution
What is an important determinant in drug distribution?
Protein binding
What is an example of high protein binding?
Ibuprofen - 99.98%
Given in a high dose - usually 400mg
What is the consequence of high protein binding drugs?
You have to give a larger dose
Change the function of the disease as well
Define bioavailability
Describes the rare and extent (amount) of a drug reaching the systemic circulation and varies from 0 (no drug absorption) to 1 (complete drug absorption)
Define clearance
The measurement of the ability of the body to eliminate a drug, one do the most important pharmacokinetic parameters
Define volume of distribution
The hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as found in the blood
Effectively a dilution factor representing the extent of drug distribution
Terminal half life
Time taken for a drug concentration to fall by one-half of its original value, used to describe elimination
Amount absorbed
Availability x dose
Amount of drug in body
Volume of distribution x concentration of drug in plasma
Concentration of unbound drug in plasma
Fraction unbound x concentration of drug in plasma
Rate of elimination
Clearance x concentration of drug in plasma
Rate of elimination
Elimination rate constant x amount of drug in body
Rate of renal excretion
Renal clearance x concentration of drug in plasma
Rate of renal excretion
Fraction excreted unchanged x rate of elimination
What is the whole purpose of drug metabolism?
Make the drug more soluble so it can be eliminated in the urine
Biliary elimination
Can come down in the bike and goes eliminated in the faeces
Conjugation
CYP450 will put a hydroxyl group on it
What is drug metabolism pathway?
- Phase I - functionalization
2. Phase II - conjugation
What are examples of phase I - Functionalization
- Hydrolysis reactions
- Oxidation
- reduction
CNS target
You want a certain amount of lipophilicity and certain amount of greasiness
What is an example of CYP450?
Avocado
What are 4 basic P450 enzymes ?
- CYP2D6
- CYP2C19
- CYP2C9
- CYP3A4
What is CYP3A4?
Non-specific
Metabolises a lot of antibiotics
Very variable across the spectrum
What is CYP2D6?
Polymorphic
Cytochrome P450 enzymes
Super family of proteins containing harm as a cofactor
terminal oxidase enzyme in electron transfer chains
Over 50,000 distinct P450 proteins identified
What is mediated by P450?
60% of all human drug metabolism
What are drug transporters?
Specific transporters that shuttle compounds around the body
Not all about passive permeability
What are examples of drug transporters?
- P-glycoproteins
2. B-sep (bile salt exclusion protein)
What is the most important PK parameter?
Screening
Gate-keeper to a lot of PK parameter
Done In-vitro -> use battery of systems
Why screen for hepatic clearance?
- High throughout
- Readily obtain human data
- microsomes, S9, hepatocytes, bactosomes - Better define “mechanistic” pharmacokinetics
Intrinsic clearance
CLi = k.Vd
What are the In-vitro approaches?
- Intrinsic clearance screens
- measure innate metabolic stability
- ml/min/g liver
- tank order - Correction with Fub
- fraction unbound in blood
- CLi * Fub
- corrected rank order - Scale up and apply model of hepatic function
- prediction of in vivo clearance
- correlate with known in vivo data
What are the optimal physio chemical properties which are essential for good permeation?
- Size
- Polarity - pKa
- Hydrogen bonding capacity
- PSA
- Ionised groups
- Lipophilicity
- Solubility
What is Lipinski rule of 5
Optimal oral permeation achieved when:
- No more than 5 H-bond donors
- No more than 10 H-bind acceptors
- Molecular weight < 500da
- LogP < 5
What are the physio chemical properties
- Solubility
2. Lipophilicity
Solubility
- Druggist be in solution to get across membrane
- Insoluble drugs
- dissolution rate limiting absorption
- poor pk profile - may not even work
Lipophilicity
- Can be measured
- Octanol/water partitioning Coefficients
- logP = [octanol]/[water]
- can be calculated
- Hansch, Moriguchi alogrithm
Polar drugs
Rapid excretion
Lipophilic drugs
Rapid metabolism
What can clearance of compounds be?
- Renal
- Metabolic
- Transport mediated
What does metabolism convert?
Molecules capable of crossing biological membrane into molecules voided in the ruins
What is the major factor in determining clearance route?
Lipophilicity
Compounds with log D7.4 below 0
Significant renal clearance values due to low reabsorption across tubules
Compounds above log D7.4 of 0
Undergo metabolism
