Biopharmaceutics Flashcards
What are some of the challenges of oral drug delivery?
PHYSIOHEMICAL PROPERTIES:
- Poor aqueous solubility
- pH dependent solubility
- Increased lipophilicity
- Increased Molecular weight
PHYSIOLOGICAL BARRIER:
- Mucus barrier
- Disease ph range in the gi tract (1.2-7.4)
- 1st pass metabolism
- digestive enzymes
BIOPHARMACEUTICAL BARRIERS:
- Poor drug permeability
- Drug efflux transporters
CLINICAL BARRIERS:
- Disease state
- Differences in gastric emptying/GI transit time
- Differences in oral bioavailability
Describe the role of mucus in the body?
Is a ubiquitous protective barrier (ubiquitous = found everywhere)
- Any wet surface on the body has a mucus layer which protects the epithelium against particulate damage and pathogenic attacks
- Acts as a lubricant
- Hosts bacteria
- Allows selective nutrient passage
- Barrier to oral or nasal delivery of drugs
What are some conditions that characteristically have absence of mucus?
- Absence in GI tract= collitis
- Dry eye syndrome
- Modification to mucus in the respiratory tract = cystic fibrosis
What are mucins?
O-glycosylated glycoproteins that form a stiff, extended polymer structure (like a gel) to aid lubrication and barriers.
- They can be membrane-bound or secreted into the mucus
They are different/made of different proteins depending on where they are found in the body e.g. in small + large intestine = MUC2
Can nanoparticles pass through mucus?
yes- diameter smaller than 200nm can easily pass freely through the mucus
Discuss the drug permeability across the intestinal mucosa?
Requires a steep concentration of drug gradient- if a high concentration of drug close to the epithelium, there is an increased chance of being absorbed into the epithelium
Need careful control of release of drug:
- Too fast: drug doesn’t reach epithelium
- Too slow: The concentration gradient is far too shallow so drug is unable to cross the epithelium
Ideal release time profile = 2-3 hours
Needs to cross the mucus barrier at the epithelium:
2 ways
- Mucoadhesive: Drug or carrier adheres to the mucus and is carried with it along the GIT. Drug moves at speed of mucus and is retained for lifetime of mucus.
BUT, The mucus is turned over the epithelial layer and out into the lumen. However, drugs want to go the other way- against the mucus flow
- Mucopenetrant- the drug penetrates the mucus to get into the epithelium.
BUT, this is very difficult as it is hard to prevent mucoadhesion and so need nano-sized vehicles with a disguise e.g PEGylation
What are the 5 routes to drug absorption across the mucosa?
From lumen –> systemic circulation
Transcellular route- passive diffusion
Paracellular route- Tight junctions- passive diffusion
Transcellular route- active transporter
Lipid absorption via micelles or bile salts
Particulate absorption via GALT
Discuss the passive transcellular route
- Passive diffusion of drug:
Requires a high conc of drug near epithelium so it can move to the low conc inside the cell ( diffusion gradient) - The drug diffuses into the epithelial cell and then out the other side into the blood for systemic circulation
- This is the way most drugs work
- LogP is important- as drug needs to partition into the membrane- needs some lipophilicity:
Absorption depends on lipophilicity - As logP increases, so does the activity
UNTIL, a max logP is reached= too lipophilic to partition out of the cell on the other side (into blood)
What is LogP?
it measures how much of a solute dissolves in the water portion versus an organic portion. Solutes that are predominantly dissolved in the water layer are called hydrophilic (water liking) and those predominantly dissolved in lipids are lipophilic (lipid liking
- A negative value for logP means the compound has a higher affinity for the aqueous phase (it is more hydrophilic)
- when logP = 0 the compound is equally partitioned between the lipid and aqueous phases
- a positive value for logP denotes a higher concentration in the lipid phase (i.e., the compound is more lipophilic)
Discuss the paracellular route (tight junctions)?
Tight junctions are gaps between cells that can allow drugs to pass through.
Drugs have to be small- as pore size is just 0.8nm in the jejunum and 0.3nm in the ileum and colon
- Drugs must be small and hydrophilic molecules with a molecular diameter 1.15 nm
e.g. mannitol, lactulose
Discuss the transcellular route?
Exploits the use of active transporters used for the transport of natural substances in the body e.g. amino acids and vitamins
- The drugs move AGAINST a concentration gradient- from low to high conc
e.g. Levodopa uses amino acid transporter, ACE inhibitors use oligo peptide transporters
Discuss drug/lipid absorption via micelles/bile salts route?
Mechanism:
The biles salts are secreted into the small intestine, where they emulsify lipid molecules- lipids are hydrolysed by lipases to monoglycerides and fatty acids
- The monoglycerides, fatty acids and bile salts are all mixed together to form micelles
- The lipid molecules (lipid drugs?) are absorbed into micelles and then can partition from micelles into the cells
e.g. poorly-water soluble drugs = fat soluble
- drugs need a high logP
Discuss the particulate absorption via GALT route?
GALT = Gut-associated lymphatic tissue
MOA:
This occurs in the Peyer’s patches of GALT in the small intestine
- The M-cells samples the contents of the lumen by taking up material and transporting it to the lymph system - absorption into the lymphatic system = eventual distribution to liver or spleen
e.g. macromolecules, microparticulates (<10 micrometers)
don’t really understand-look into more
What factors act agains the absorption of drugs from the GIT lumen into epithelium?
Proteins that remove drug from cell back to lumen e.g. P-glycoproteins (found membrane-bound in the apical membrane) and CYP3A4 (found in brush border of the small intestine) are both found in intestinal enterocytes
- CYP 3A4 decreases the amount of drug absorbed throughout GI tract
- P-gp- acts to remove drug back into the intestinal lumen- recognised drugs as toxic materials e.g. can cause resistance in tumour cells as ir removes drugs administered to treat cancer as acts as efflux transporter
= BOTH DECREASE SYSTEMIC EXPOSURE OF DRUGS
What are examples of drugs that are inhibitors and inducers of CYP 450 3A4?
INHIBITORS
- Ketoconazole
- Grapefruit juice- can increase absorption of drug = overdose
INDUCERS
- Rifampicin
- Phenytoin
- Dexamethasone
- Phenobarbitol
