W2 L1 - Introduction to ADME Flashcards
what does ADME stand for
Absorption
Distribution
Metabolism
Excretion
define adsorption
How the drug gets into the systemic blood from it’s formulation at the administered site
(Movement into body)
define distribution
Reversible transfer of drug between the blood {or other site of measurement} and other tissues within the body
(Movement around body)
define metabolism
Biotransformation of the drug into another chemical species
define excretion
Irreversible loss of drug from the systemic blood
(Movement out of body)
what’s elimination
- metabolism + excretion
- Irreversible loss of drug from site of measurement (e.g., plasma). Occurs by metabolism and/ or excretion
L and T in (L)ADME(T)
- Liberation - release of the drug from it’s dosage form
- Pharmacological effect (or toxicity, T)
is (L)ADME(T) pharmacokinetics or dynamics
pharmacokinetics
Drug and formulation properties determining absorption (oral)
- Lipophilicity
- Ionisation
- Molecular weight
- Solubility
- Permeability
- Formulation
- Excipients
- Enteric coating
- Controlled release
- Particle size
Drug and formulation properties determining absorption (subcutaneous)
- Molecular weight < 16 kDa: Diffusion/ permeation through capillary wall is dominant route of absorption
- Molecular weight > 16 kDa: Lymphatic system is dominant route of absorption
what does distribution determine
- drug concentration in blood plasma and different tissues
- unbound drug conc drives effect
define tissue perfusion
- a certain blood volume flowing through a given tissue volume over a period of time
- highly perfused: Lungs, kidneys, liver, brain
Equilibrium - Fast - poorly perfused: Muscle, skin, adipose
Equilibrium - slow
How are unionised and lipophilic drugs distributed
- Cross cell membranes easily
- Partition into lipid spaces of tissues (e.g., membranes) and bind neutral lipid/ phospholipid (NL/NP)
How are ionised drugs distributed
- Basic drugs (BH+):
- Electrostatic interactions with tissue acidic phospholipids (AP-)
- Prone to lysosomal trapping (pH partitioning)
- Acidic drugs bind to extracellular proteins (PR)
Distribution: Plasma protein binding
- unbound drug conc drives effect
- large plasma proteins not permeable
- allows measurement of drug binding using analysis
- key drug-binding plasma protein = albumin
Why a difference between the total and unbound concentrations with respect to the reference range?
- Some patients have hypoalbuminemia (low concentration of albumin in plasma
- some drugs have saturable (non-linear) protein binding - when a drug binds to plasma proteins until binding sites are full, after which small dose increases cause disproportionately high free (active) drug levels, increasing the risk of toxicity
Key sites for first-pass drug metabolism
- liver and intestines
key sites for metabolic elimination
- liver
- brain
- lung
- kidney
- blood
are lipophilic drugs more or less likely to be excreted
more likely
how do metabolites differ to their parent drug in terms of chemistry
- more polar
- less lipophilic
Factors affecting drug metabolism
- pregnancy
- age
- gender
- polymorphisms
- diabetes
- liver + kidney diseases
routes used in drug excretion
- urine - glomerular filtration, active secretion, active/passive reabsorption - hydrophilic, uncharged drugs
- bile - active secretion - hydrophilic, uncharged drugs
- lung - passive diffusion - gaseous and volatile drugs, insoluble in blood + tissue
- saliva - pd - active transport - unionised, lipophilic drugs
- breast milk - pd - ‘’
- sweat - pd - ‘’
