Unit 2 - Biological barriers & ADME 1 Flashcards
Give five ways of transport across a biological barrier
Passive transcellular Passive paracellular Vesicular Efflux Metabolism
What are tight junctions made from?
Proteins between two cells forming non-covalent bonds
What is passive transport limited by?
Availability of an electrochemical gradient and suitable drug physiochemical properties for permeability
What are solute carriers limited by?
Selectivity of transporter for chemical features of substrate and availability of electrochemical gradient
What are active efflux carriers limited by?
Selectivity of transporter for chemical features of substrate
- driven by primary energy source
What is vesicular movement important for?
Limited importance for small molecules
Important for proteins/peptides
- endocytosis
- transcytosis
What is metabolism limited by?
Selectivity of enzyme for chemical features of substrate
Give examples of types of epithelial barriers
Simple squamous - lung alveolar type I Simple cuboidal - lung alveolar type II Simple columnar - kidney proximal tubule Stratified squamous - buccal - non-keratinised - skin - keratinised Stratified cuboidal - glands and ducts Stratified columnar Pseudostratified columnar - conducting airways of lung - intestine - nasal cavitiesSimple squamous - lung alveolar type I Simple cuboidal - lung alveolar type II Simple columnar - kidney proximal tubule Stratified squamous - buccal - non-keratinised - skin - keratinised Stratified cuboidal - glands and ducts Stratified columnar Pseudostratified columnar - conducting airways of lung - intestine - nasal cavities
Which type of molecules don’t readily partition into cell membranes?
Hydrophilic molecules
How do hydrophilic molecules cross epithelial barriers?
Paracellular transport
Which type of molecules permeate easily across cell membranes?
Hydrophobic molecules
How do hydrophobic molecules cross epithelial barriers?
Transcellular transport
- large surface area
Give some examples of types of capillary
Continuous capillaries
Fenestrated capillaries
Discontinuous capillaries
How do normal capillaries allow paracellular diffusion of small molecules?
Cell junctions are not tightly sealed
Which barrier is the exception to capillary endothelium cells not being tightly sealed?
Blood Brain Barrier
What is a continuous capillary?
Epithelial cells that are held together by tight junction with intercellular clefts to allow fluid passage
What is a fenestrated capillary?
Perforated by fenestra bearing thin diaphragm
- glomerular capillaries
What is a discontinuous capillary also known as?
Sinusoids
What is a discontinued capillary?
Contains inter-endothelial gaps >100nm wide
Discontinuities in the basement membrane as well
- liver sinusoids
- movement of macrophages and large particles
What molecular properties effect the process of how a molecule will cross a membrane (e.g partitioning, diffusion, stability within barrier)?
Steric; molecular size, volume, shape
Hydrophobicity; lipid/ water
Ionic properties; Hydrogen bonding potential, pKa
What is solubility?
Property of a solid to dissolve in a liquid to form a homogenous solution
solubility depends on the:
- physical and chemical properties of the solute
- temperature
- pressure
- pH of solution
What is permeability?
Property of a membrane to allow passage of a solute
- permeability depends on the
- physical and chemical properties of the solute
- physical and chemical properties of the membrane
- temperature
- pH of solution
What is partition coefficient, P?
Measure of the differential solubility between octanol/water for neutral compounds or where the compound exists in a single form
What is partition coefficient, D?
Appropriate descriptor for ionisable compounds as it is a measure of the pH dependent differential solubility of all species in the octanol/water system
What is LogD dependent on for ionisable compounds?
pH and pKa
- distribution of charged and uncharged forms will change
What are the two types of superfamilies of transporters present in cell membranes?
ATP-dependent Binding Cassette (ABC) binding proteins Solute carriers (SLC)
Give some examples of ATP-dependent Binding Cassette (ABC) binding proteins
P-glycoprotein - P-gp Multidrug Resistant Proteins - MRPs Breast Cancer Resistance Protein - BCRP
Give some examples of Solute Carriers (SLC)
Organic cation transporters - OCTs Organic cation/carnitine transporters - OCTNs Organic anion transporters - OATs Organic anion transporting polypeptides - OATPs Peptide transporters - PEPT1 - PEPT2 Amino acid transporters Monocarboxylate transporters
google pka and ionisaion
ghg
Where does P-glycoprotein expression increase in the apical (luminal) plasma membrane of small intestine enterocytes?
From proximal to distal regions of the small intestine
What factors affect the impact of P-glycoprotein?
P-gp expression and affinity for a drug
- higher pull through membrane
Passive membrane flux
- bypass P-gp
Where is P-glycoprotein constitutively expressed?
Blood Brain Barrier
Lung epithelium
Kidney
Liver
Give some examples of where integral membrane proteins found
Plasma membrane
Mitochondria
Intracellular organelles
What is a secondary active transporter?
Transporter protein couples the movement of an ion (typically Na+ or H+) down its electrochemical gradient to the uphill movement of another molecule or ion against a concentration/electrochemical gradient
What is a symport carrier?
A cotransporter carrying 2 molecules in the same direction (either into or out of the cell)
What is an antiport carrier?
A cotransporter carrying 2 molecules in different directions
