D8 - drug absorbtion Flashcards
Pharmacokinetics
- Branch of pharmacology that concerns itself with what the body does to the drug
- Why does it matter
○ A drug needs to have properties that allow It to reach the tissue where the receptors are that it has to bind
○ Knowing how much/how often to give a drug
- Why does it matter
Pharmaceutical phase
- Ingestion
- Disintegration and dissolution
Absorption routes
- How it gets from site of administration into the systematic circulation
- Enteral route (oral)
a. Easiest and most common - used 80% of the time
b. Also includes
i. Buccal - putting a pill against the cheek
ii. sublingual routes - putting the pill under the tongue
c. Safest due to protection of GI tract and liver - barriers protecting the body
d. Drugs encounter barriers - GI wall, blood vessel walls, - Parenteral route (non-oral)
a. Any non-oral route
b. Bypass protective effect of the liver/GIT
c. Less safe - bypasses protective functions of gut wall and liver
d. Requires clinical environment - usually cannot be done at home
e. 4 routes (syringes at different angular injection and depth of delivery of the needle)
i. Intramuscular
ii. Subcutaneous
iii. Intravenous
iv. Intradermal
- Enteral route (oral)
- Enteral route (oral)
a. Easiest and most common - used 80% of the time
b. Also includes
i. Buccal - putting a pill against the cheek
ii. sublingual routes - putting the pill under the tongue
c. Safest due to protection of GI tract and liver - barriers protecting the body
d. Drugs encounter barriers - GI wall, blood vessel walls,
- Parenteral route (non-oral)
a. Any non-oral route
b. Bypass protective effect of the liver/GIT
c. Less safe - bypasses protective functions of gut wall and liver
d. Requires clinical environment - usually cannot be done at home
e. 4 routes (syringes at different angular injection and depth of delivery of the needle)
i. Intramuscular
ii. Subcutaneous
iii. Intravenous
iv. Intradermal
e. 4 routes (syringes at different angular injection and depth of delivery of the needle)
i. Intramuscular
ii. Subcutaneous
iii. Intravenous
iv. Intradermal
Oral drug absorption
○ Occur along the length of GI
§ Mostly in practise occurs in the upper small intestine - duodenum
§ Because it has a long length and massive surface area
§ Well vascularised and high perfusion - drug uptake is effective
§ Folds and villi increase surface area 600 fold
○ Drugs encounter different environments as they transit the GI tract
§ PH, enzyme expression, fluidity of contents (eg. Acidic stomach)
§ Implications for ionisable drugs - amines, carboxylic acids
How are drugs absorbed
- Traditional view
○ Most small amphipathic drugs (drugs that are slightly water soluble and slightly lipid soluble) diffuse via transcellular route - diffuse across the membrane of epithelial cells lining the GI tract
§ Not to big, lipid and water solubility, ionisation status
○ Very small hydrophilic drugs enter via paracellular route
§ Via gaps in tight junctions at the interface of cells
§ Eg. Alcohol- Newer view
○ Membrane drug transporters - control drug influx(out of the lumen into the enterocyte)/efflux (removing drugs and returning them to the lumen) on basolateral membrane (drugs on basolateral membrane - moving drugs into the blood stream) and across cell membranes
§ SLC (solute carriers ) - assist passive drug transport
□ Facilitate transport in any direction - passive drug transport (facilitated transport)
§ ABC Class transporters - ATP - dependant transport (active transport)
○ Transported expression varies in different anatomical settings
- Newer view
influx SLC
- Most are bidirectional solute carrier class - SLC
* Able to move cationic (amines) ions and anionic ions (acids)
Efflux ABC
• ABC type
• Unidirectional - only pump drugs out of cells
• Important in tumour cells - often confer resistance on tumours by pumping drugs out of tumours
• P-glycoprotein
○ Major role in GI drug absorptions
○ Also called ABCB1
○ Gut wall
P- glycoprotein
○ P-gp is clinically significant
§ ATP-dependant pump that decreases oral absorption of many lipophilic drugs
§ Pumping action driven by ATP hydrolysis
§ Drug pumped out across the membrane - efflux pathway
○ Member of ATP binding cassette ABC type
§ Encoded by ABCB1 gene
○ Strongly expressed in GI epithelium
§ Acts as efflux transporter to return absorbed drug to gut lumen
§ Hundreds of drugs are substrates for this - ideally these would be reduced
○ Expressed at liver canaliculi, BBB, proximal tubules, proximal tubes. placenta, testes
○ Drugs that are substrates for this proteins have limited absorption because they get pumped out of cells
Factors controlling drug absorption
- Transcellular transport in GI-tract is influences by the physiochemical properties of drugs
- Lipinski’s Rule of Five
○ Molecular mass less than 500g/mol
○ Calculated log octanol/water partition coefficient (LogP) of 5 or less (a measure of drug lipophilicity)
○ Less than 5 hydrogen bond donors (ie. Sum of OH and NF)
○ < 10 H-bond acceptors (sum of O and N atoms) - For good drug absorption, drugs should meet these 4 criteria
- Lipinski’s Rule of Five
Lipinski’s Rule of Five
○ Molecular mass less than 500g/mol
○ Calculated log octanol/water partition coefficient (LogP) of 5 or less (a measure of drug lipophilicity)
○ Less than 5 hydrogen bond donors (ie. Sum of OH and NF)
○ < 10 H-bond acceptors (sum of O and N atoms)
Lipophilicity
a. LogP
§ Assesses partitioning behaviour of drug in simple biphasic system: water and octanol (model 8-carbon solvent)
§ LogP value needs to be less than 5
§ Must not be too lipo/hydrophilic - must have a good balance
§ Molecule should be spread somewhat evenly in the two layers
b. Polar surface area (PSA) i. Surfaces of drug molecule can contain polarised atoms (usually O or N) ii. Computational PSA prediction calculates sum of tabulated surface contributors of polar fragments - how much surface area is occupied by polarised atoms - if a molecule is too polar it wont be able to penetrate 1) PSA estimates can predict human intestinal absorption of drugs 2) PSA also predicts toxicity, protein binding, receptor promiscuity
LogP
§ Assesses partitioning behaviour of drug in simple biphasic system: water and octanol (model 8-carbon solvent)
§ LogP value needs to be less than 5
§ Must not be too lipo/hydrophilic - must have a good balance
§ Molecule should be spread somewhat evenly in the two layers
b. Polar surface area (PSA)
i. Surfaces of drug molecule can contain polarised atoms (usually O or N)
ii. Computational PSA prediction calculates sum of tabulated surface contributors of polar fragments - how much surface area is occupied by polarised atoms - if a molecule is too polar it wont be able to penetrate
1) PSA estimates can predict human intestinal absorption of drugs
2) PSA also predicts toxicity, protein binding, receptor promiscuity
Egan’s egg
§ Statistically, orally administered drugs fall within an egg shaped distribution of LogP and PSA values
Drug ionisation and drug absorption
○ Drug often contain ‘functional groups’ that can adopt positive or negative charge
§ Allows drugs to be classified as either acids or bases
○ Acids
§ Carboxyl group which is ionised at near neutral
§ Ionised in duodenum
○ Basic
§ Often has nitrogen atoms which carries a positive charge in acid
§ Non-ionised in neutral
§ Ionised in stomach
○ Only non-ionised can diffuse across lipid membranes § Bases mainly absorbed in duodenum § Acids absorbed in stomach (but still mostly duodenum because of surface area) § Overall, mostly duodenum because of massive surface area
