biopharmaceuticals Flashcards
what are the four barriers to oral drug delivery
physiochemical - pH/lipophilicity physiological - mucus clinical - disease states biopharmaceutical - efflux transporters
what is the role of mucus
ubiquitous protective layer against physical, pathogenic attack and lubrication
what is mucus made of
mucins, water, salts bile acids and proteins
what are mucins
highly o-glycosylated glycoproteins that are highly extended, free or membrane bound on epithelial surface
what type of mucus is found in the intestines
MUC2
what type of mucus is found in the airway
MUC5
what type of mucus is found in the cervix
MUC5B
what is the intestinal mucosa like and how does this affect drug delivery
SI - thin allows small molecules through LI - thick, nothing through need to create steep drug gradient at point of absorbance
what are the two approaches to getting drugs through the mucus layer
mucoadhesive and mucopenetrant
how do mucoadhesive drugs work
adheres to mucus as it moves down the GIT, released on the way
how do mucopenetrant drugs work
penetrates mucus to get to epithelium - requires nano-sized vehicle with stealth coating - such as PEG
what are the 4 routes of drug delivery from intestinal lumen
transcellular via passive diffusion paracellular via tight junctions transcellular via active transport lipid absorption via micelles/bile salts particulate absorption via GALT
how are drugs absorbed via transcellular via passive diffusion from the intestine
- High conc on apical side of cell, low conc inside - Molecule moves into cell and then out the other side to bloodstream
how are drugs absorbed via Paracellular via tight junctions from the intestine
Tight junctions essential for GIT structure - tight junction proteins between cells, drug moves between those
how are drugs absorbed via Transcellular via active transport from the intestine
- Molecule piggybacks into cell using transporter for natural substrates - Often against a concentration gradient - Restricted to specific segments of mucosae
how are drugs absorbed via Lipid absorption via micelles/bile salts from the intestine
- Lipids hydrolysed by lipases to form mixed micelles of mono-glycerides, fatty acids and bile salts - Lipidic molecules absorbed either directly in micelle or by partition from micelle into the cell
how are drugs absorbed via Particulate absorption via GALT (gut associated lymphatic tissue) from the intestine
- Endocytosis via membranous cells in payers patches of GALT in SI- Subsequent absorption into lymph Eventual distribution into liver and spleen
what types of drugs can be absorbed Transcellular via passive diffusion
neutral, unionised drugs high LogP - if too high will not pass out other side larger molecules can pass but they are slower
what is the effect of a higher Log P on drug absorption
○ Decreased solubility ○ Increased plasma protein binding Increased binding to non-target sites
what are three drugs that are absorbed transcellularly via diffusion
propranolol - LP: 2.6testosterone - LP : 3naproxen - LP : 3.3
what types of drugs can be absorbed Paracellular via tight junctions
small hydrophilic
what are two drugs that are absorbed Paracellular via tight junctions
cimetidine - LP : 0.4atenolol - LP : 0.2
what types of drugs can be absorbed Transcellular via active transport
- Levodopa/D-Cycloserine utilise amino acid transporters ACEi utilise oligo 2-3 peptide transporter
what are three drugs that are absorbed Transcellular via active transport
- Cefalexin (LogP : 0.7) - Levodopa (LogP : -2.4) - Captopril (LogP : 0.3)
what types of drugs can be absorbed Lipid absorption via micelles/bile salts
poorly water soluble drugs
what types of drugs can be absorbed Particulate absorption via GALT (gut associated lymphatic tissue)
- Macromolecules - Microparticles (>10um)
what two enzymes can reduce drug absorption in the gut
CYP and P-gp
what does CYP do to reduce drug absorption
acts to reduce the amount of drug absorbed into the gut
what does P-gp do to reduce drug absorption
ATP dependent, saturable efflux pump, pumps drug back into intestinal lumen
what issues are associated with CYP enzymes
- Many drugs act as a substrate, structurally diverseLarge interpersonal variation in levels of CYP3A4
what are some cyp inhibitors
ketoconazole grapefruit juice
what are some CYP inducers
rifampicin phenytoin dexamethasone phenobarbital
what are some issues with p-gp
- Structurally diverse substrates - Compounds can be both inducers and inhibitors - Overlap with CYP
what inhibits P-gp
verapamil ketoconazole tweens PEGs
what induces P-gp
rifampicin phenytoin dexamethasone phenobarbital
