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)
