Basic principles of drug ADME Flashcards
Define pharmacokinetics.
Movement of a drug:
- Into the body (ABSORPTION) - across physiological barriers
- Around the body (DISTRIBUTION) - to reach its target tissues
- Out of the body (ELIMINATION)
Describe the principle of pharmacokinetics.
The drug’s ability to access its target is limited by:
* Metabolism:
– body inactivates the drug(enzymatically)
* Excretion:
– body gets rid of the drug (via kidney or in the faeces)
Why do we need pharmacokinetics?
- Tells us the correct dose of a drug which is needed to reach the target site at a
concentration high enough to cause an effect and low enough to avoid side effects - For each drug the “right” dose is different
Creates the need to know the pharmacokinetic properties for each drug - PK data of each drug allows us to calculate the correct dose
What knowledge does a drug PK give us?
- Which dose to give
- Which administration route to choose
- How often to give a dose (frequency)
- Which administration formulation to choose for a drug
State the stages of drug discovery.
- Identify
target side - New drug
synthesis
State the stages of preclinical experiments.
- In vitro (cell model)
and in vivo (animal
model) experiments - Testing drug activity
- First PK and PD data
State the stages of clinical trials.
- Phase I: Safety and Dose range
identification (small number of
participants), PK, PD, Dose range - Phase II: Safety, Efficacy, Dose range,
target disease population (higher
number of participants) - Phase III: Efficacy and Comparison,
(bigger number of participants)
What is ADME?
Absorption = Mass transfer process involving the movement of unchanged drug molecules from the site of administration into the blood stream
Distribution = once a drug reaches the blood stream it will get distributed across different compartments in the body
Metabolism = Being distributed the drug will reach sites where it is metabolised
Elimination = drug is excreted from he body and passed out via excretion organs
How are drugs transported across membranes?
- Active transport
- Passive diffusion
- Facilitated passive diffusion
- Endocytosis
Describe the structure of cell membranes.
- Membranes consist of phospholipids (PL) with hydrophobic tail and hydrophilic head - containing a phosphate group
- Many integral proteins in the membrane
- Integral proteins are amphipathic (with polar and non-polar groups)
- Cell membrane permeable to small non-polar molecules
- NOT permeable to molecules with:
- High polarity
- High molecular weight
- Conformational freedom
Describe simple diffusion across membranes.
- Transcellular route is used spontaneously
- No involvement of any membrane protein
- Slowest step of the absorption process
- Large molecules will diffuse more slowly than smaller ones
What is first order kinetics (simple diffusion)
Concentration of of drug is directly proportional to the rate of absorption
Why is first order kinetics important (simple diffusion)?
Helps to sustain a conc. gradient
Describe facilitated diffusion.
= passive mediated transport
* Process of spontaneous passive transport of drugs across a biological
membrane via specific transmembrane integral proteins
* Transmembrane proteins: channel proteins and carrier proteins
* Number of molecules transported depends on the number of proteins
Describe channel proteins.
- Form open pores in membranes
- Small molecules also pass
between adjacent cells
connected as tight junctions
Describe carrier proteins?
- Bind specific drugs and as a consequence undergo
conformational changes that allows molecules to pass through
Which molecules pass via facilitated diffusion?
- Sugars, amino acids, nucleosides
- Only drugs with similar structures passes through facilitated diffusion (e.g.
levodopa, Methyldopa, Tyrosine, 5-Fluoruacil)
What are the different active transporters?
- Uniport
- Antiport
- Symport
Describe uniport active transport.
- Mediate the transport of a single drug/ substance
- Facilitate the mode of diffusion accelerating a reaction that is already
thermodynamically favoured - Allows transport of non-diffusible substances across the membrane at a much
higher rate than passive diffusion
*Molecules/drugs/substances are never in contact with the hydrophobic core of the
membrane
Describe antiport active transport.
- Ability to couple the movement of one substance with another against the
concentration gradient
Describe symport active (co-transport)
- Ability to transport two different substances simultaneously
State the parameters that influence absorption.
- Physiochemical properties of the drug (e.g. hydrophilic,
lipophilic, size, acidity) - Pharmaceutical dosage form (e.g. sustained release forms)
- Anatomical and physiological characteristics (e.g. Body weight,
Age, Sex) - Administration route (systemic or topical)
Define dose
- A specific measured amount of a drug which is needed to reach a specific plasma concentration
What is plasma concentration?
- The amount of drug which reaches the blood stream and gets distributed in the body
- this specific plasma conc. reaches the target site and has a pharmacological effect
What does the way a drug is administered determine?
The time a drug needs to reach the blood flow.
What does the area under the curve represent?
- Actual body exposure to drug after administration of a dose
- Expressed in mg*h/L
- Determined by dose, clearance and bioavailability
What is meant by bioavailability?
Amount of drug reaching circulatory system from delivery system used.
Describe bioavailability for oral administration.
Depends on the absorption rate.
Describe bioavailability for intravenous administration.
Is 100% as it is administered directly into circulation.
State the factors that influence bioavailability.
- Lipid solubility and chemical form of a drug - salt factor
- Formulation - bioequivalence
- Physiochemical properties
- Co-administration of other drugs
- Presence of comorbidity affecting absorption sites (e.g. diarrhoea, vomiting)
- Susceptibility to gastric acid and digestive enzymes
- Degree of metabolism in gut mucosa and first-pass effect
What does bioequality ensure?
That all the drug formulation on the market have the same bioavailability
What is meant by drug distribution?
Reversible mass transfer
of a drug from one
location to another within
the body
What happens once h drug has been absorbed?
There will be a conc. gradient between absorption site and conc. gradient
What is drug distribution dependent on?
Blood flow
What is the importance of a drug being more lipid soluble?
The higher the chances of reaching the target
What must the drug pass through and why?
The capillary walls and into interstitial fluid to be able to interact with cell surface receptors.
How does molecular weight influence distribution?
Large molecules are more difficult to cross membranes than smaller ones.
How does polarity influence distribution?
Polar molecules will face difficulties to move through simple diffusion.
How does degree of ionisation influence distribution?
Charge of molecules will depend on ionisation and the pH of environment.
How does affinity of drug to transporters influence distribution?
- Some drugs are only transported by specific transporters
- Two substrates compete for the same enzyme binding position
How does expression level of drug transporters influence distribution?
Physiological factors are subjects in individuals in a healthy and ill state
How does the characteristics of capillary bed influence distribution?
- Permeability and numbers of tight junctions are different across tissues
- Three different capillary beds - continuous, fenestrated and sinusoid capillary
How does tissue and organ perfusion influence distribution?
Blood flow to a given organ/rate at which blood perfuse a specific organ measures in volume of blood per unit of time per unit of tissue mass
Describe how affinity between the drug and tissue influence distribution?
Depends on the unspecific interaction that occur between the drug and tissue elements e.g. vascularity, fat content, pH
What factors influence blood flow?
- Exercise:
* Cardiac output increases 5 to 6 times
* Perfusion increases and with it drug distribution - Concomitant diseases:
* Patients with heart failure not enough perfusion
* Drug distribution takes longer
* Peak response of a given dose is delayed - Decrease in renal clearance
* Reduction in renal and hepatic perfusion delay drug excretion - Shock
How do drugs bind?
- Ionic bound
- Hydrogen bound
Describe ionic binding of a drug.
- Association of ions of opposite charge by the transfer of electrons from one to
another - Bounds are weak -> easily broken through the induction of a different ion
with a greater affinity - Example: phenytoin sodium (weak acid, ↑ pH ionizes, ↓ pH forms a salt
and preticipates)
Describe hydrogen binding of a drug.
- strongest bound
- Determines the way a drug interacts with target molecule, metabolic enzymes,
transport proteins - Determines the degree of binding to plasma proteins (e.g. albumin)
- Binding is reversible, concentration dependent and subject to competition with
other drugs/ substances
Describe plasma protein binding.
Drugs may be held in plasma compartments by:
1. Albumin
2. Lipoprotein
3. α1- acid glycoprotein
Describe the binding of drugs to albumin.
- Most weak acids bind to albumin
- Albumin has 2 binding sites
- Binding is reversible and at therapeutic concentrations unlikely to be saturable
How to calculate fraction of unbound drug?
unbound concentration/total drug concentration
What is volume of distribution?
Describes how well a drug is distributed
How to calculate Volume of Distribution?
Dose of drug(mg) / Drug serum conc. (mg/L)
What does volume of distribution vary with?
Body weight
What does volume of distribution depend on?
Plasma protein binding - drugs with low VD are currently highly bound to plasma proteins
