Bench to bedside Flashcards
What are the physicochemical barriers to drug delivery?
Poor aqueous solubility
pH dependent solubility
Extensive ionisation at GI pH range
Extreme lipophilicity
High molecular weight
Susceptibility to pH mediated degradation
What are the physiological barriers to drug delivery?
Mucus barrier
Diverse pH range of the GI tract (1.2-7.4)
Rapid gastric emptying
Gastric and intestinal motility
First-pass metabolism
Presence of digestive enzymes
GI microflora and their secretions
What are the biopharmaceutical barriers to drug delivery?
Poor drug permeability
Pre-systemic metabolism in the GI tract
Presence of drug efflux transporters
pH and mucosal layer thickness variations in the GI tract depending upon the location
What are the clinical barriers to drug delivery?
Fed and fasted state variability in drug absorption
Inter/Intra individual differences in oral bioavailability
Difference in gastric emptying time and GI transit time
Disease state
What does the mucus barrier do?
Protect cell surface from pathogens and harm and allow passage of substance, the absence of this can lead to colitis in the GI tract, dry eyes and when mucus is overproduced can cause CF in respiratory which leads to inflammation and infection
How is the mucus barrier formed?
Mucins are thick extended glycoprotein polymers which have sugar side chains. They are made in the endoplasmic reticulum and transported to the golgi and glycosylated.
What part of the intestine has a large dense layer and bacteria cannot penetrate it?
Large intestine
What art of the intestine has one layer which bacteria can penetrate it easily?
Small intestine
How do drugs get across the intestinal mucosa?
-Stop concentration gradient just outside the point of absorption
-Careful control of release of the drug
Where do fast release drugs stay?
Doesn’t reach epithelium stays in the lumen
Where do slow release drugs stay?
Concentration gradient is too shallow and does not cross the epithelium, therefore not absorbed.
What are the two ways in which we can deliver drugs across the mucus barrier?
1) Mucoadhesive
2) Mucopenetrant
What are mucoadhesive drugs?
-Drug/carrier which sticks to mucus and is then carried along the GIT an the drug is released along the way, the drug is then retained for a lifetime of mucus transit and has to pass through mucus which goes agasint the flow.
PRO of mucoadhesive drugs?
Doesn’t get maintained in the lumen
CON of mucoadhesive drugs?
Drug has to go against the mucus
How do Mucopenetrant drugs work?
Drug/carrier which penetrate though the mucus to get to the epithelium.
PRO of mucopenetrant drugs?
Gets to epithelium
CONs of mucopenetrant drugs
Difficult to avoid muco-adhesion, therefore need to have a nano-sized vehicle with a ‘stealth’ coating, such as PEG
What are the 5 routes to drug absorption across mucosae?
1) Transcellular route - passive diffusion
2) Paracellular route (passive diffusion)
3) Transcellular route (Active transporter utilisation)
4) Lipid absorption via micelles/bile salts
5) Particulate absorption via GALT
What is the mechanism of transcellular route for drugs to cross the mucosae?
- Mechanism: Passive diffusion (Fick’s law)
- High concentration on apical side of the cell
-Low conentration inside the cell
-Molecule diffuses into the cell and out the other side into the blood
Tries to equalise
What drugs use the transcellular route?
-Most drug molecules
-Neutral molecules (un-ionised)
-logP is important, as it needs to partition into the membrane, need to be reasonably high
What is the mechanism of the paracellular route?
Absorption through tight junctions
What is the pore size in paracellular route?
Jejunum and small intestine 0.8nm, ileum and colon 0.3nm
What drugs use the paracellular route?
Small hydrophobic molecules of molecular diameter less than 1.15nm. Example: Mannitol, PEG 400, Lactulose
What is the mechanism of the transcellular route?
Molecule ‘piggybacks’ into the cell using a system designed for natural substrates such as amino acids and vitamins, this is often against a concentration gradient. These use the cells own physiology to get into the cell.
What substrates use the transcellular route?
L-dopa and D-cycloserine utilise the amino acid transporter, ACEi utilise the oligo 2-3 peptide transporter (PEPT transporters)
What is the location of the transcellular route?
Apical brush border membrane of intestinal epithelium, restricted to specific segments of intestinal mucoase *example, folate transporter, vitamin B1, Bit B6, PEPT, Bile salt transporters
What is the mechanism of the lipid absorption?
-Bile salts are secreted into the small intestine to emulsify lipid molecules
-Lipids are hydrolysed by lipases to give monoglycerides and fatty acids
-Formation of mixed micelles of mono-glycerides, fatty acids and bile salts
-Lipidic molecules are absorbed either directly in micelle or by partition from micelle into the cell
-Substrates are poorly water soluble drugs (the fat soluble ones)
The body makes liposomes naturally
What drugs use the lipid absorption route?
High log p drugs
What is the mechanism of particulate absorption via GALT?
-Endocytosis via the M cells in the Peyer’s patches of GALT in the small intestine - M cells sample and transport to the lymph system
-Subsequent absorption into the lymphatic system
Eventual distribution to the liver and spleen
What substrates are involved in the particulate absorption via GALT?
Macromolecules
Microparticulate (less than 10 nano)
What factors act against absorption from the GIT lumen?
-P-gp: removes the drug back into the intestinal lumen, and can also remove drug metabolites from the cell
- Ø CTY 3A4 : reduce the amount of the drug absorbed through the gut.
= Work together to REDUCE systemic exposure
=DRUG interactions, if co-administered drugs are substrates / inhibitors / inducers of CTP 3A4 +/- P-gp
What is CYP450?
-Responsible for metabolism of drugs
-Located in the liver, small intestine (brush border) - stomach to colon levels decrease
What is the most common CYP?
CYP3A4
Where are p-glycoproteins located?
apical membrane, levels increase from the stomach to colon also in tumour cells, blood-brain barrier, kidney.
What gene codes for p-glycoproteins?
ABCB1
What are p-glycoproteins dependant on?
ATP with saturable kinetics
Why can p-glycoproteins cause resistance towards tumour cells?
Some resistance can occur in tumour cells to several anti-cancer drugs after inital treatment as it removes the drugs. It can recognise drugs as ‘toxic’, efflux transporter protein mechanism evacuate it from the cell.
What are the substrates of CYP450?
Many current therapeutic drugs
-Midazolam -Simvastatin - Ciclosporin
What are the substrates of P-Glycoprotein?
-Large and amphipathic
-Structurally diverse
-Examples: Doxorubicin, ciclosporin, tacrolimus,
What are inhibitors of CYP340?
Ketoconazole
Grapefruit juice - it increases the efficacy, = overdose risk
What are inhibitors of p-glycoprotein?
-Verapamil, ketoconazole,
-Competes for P-gp in drug cocktails
-Excipients: PEG, Tween, Surfactant, they increase absorption of drugs
What are inducers of CYP340?
Dexamethasone, Phenobarbital, Phenytoin, Rifampicin
What are inducers of p-glycoprotein?
Dexamethasone, phenobarbital, phenytoin, rifampicin
What can be a substrate and inhibitor of P-gp?
P-glycoprotein
What does a higher log do to solubility and plasma binding?
Higher logP decreases solubility, increases in plasma protein binding, increases in binding to non-target sites. Activity of the drug is increased.
What is a parabolic relationship?
Absorption and biological activity reaches a maximum.
What do tight junctions restrict?
Diffusion of polar molecules
What are responsible for fast transport of some polar molecules?
Active transporters
Why are tight junctions important?
Essential for structural integrity of the GIT epithelium
What is the structure of tight junctions?
2 cells which are next to each other, they interact as they are strongly bound together, then molecules can pass through the small gap = hydrophilic!
What route do drugs with a high log P go?
Passive transcellular route
What route do drugs with a low log P go?
Paracellular route
Cefalexin, Levodopa and Captopril all follow what route of drug distribution?
Carrier- mediated
