L3 Drug Absorption Flashcards
Drug Absorption
process by which a drug moves from its site of administration to the systemic circulation.
Explain what it means that the body is compartmentalised
drugs need to cross lipid membrane to move from one compartment
to another compartment
Transcellular
Move across a cell
- lipophilic
- passic diffusion/facilitation diffusion/active
Paracellular
Through tight junction
- low molecular weight and hydrophilic
Administration routes
Oral and Intravenous (veins)
Factors affecting oral absorption
i and ii and iii
i- Molecular Size
>oral absorption decreases as molecular weight ↑
ii- Solubility
>hydrophilicity and lipophilicity affect passive diffusion at membranes
iii- Ionisation
Two ways to estimate drug solubility
LogP - partition coefficient
Polar surface area and topological psa
LogP
Two layer solvents - organic and water then add drug and mix then allow layers to equilibrate. Then you measure drug concentration in both layers.
If more in solvent then lipophilic/ if more in water then hydrophilic
logP Values of oral drugs
less than 5
Prodrugs
medications that turn into an active form once they enter the body.
PSA
Polar surface area
sum of surface of polar atoms (N/O) in a molecule and attached to H
PSA predict
Intestinal absorption and blood-brain barrier crossing
Topological PSA
Calc the sum of tabulated surface contributions of polar fragments (computational method)
Factor affect oral - ionisation and pH dependant ionisation
many drugs classified as weak acids and based
pH-dependent ionisation of functional groups
- pKa is the pH at which drug molecules are 50% ionised
- only unionised drug molecules can diffuse passively across lipid membranes
Lipinski rule (not really important)
< 5 H-bond donors (-OH and -NH)
< 10 H-bond acceptors (-O and -N)
molecular weight < 500
the calculated logP < 5
Biological factors that affect oral absorption
- pH
- ingested food
- gut mobility
- intestinal enzymes
- transporters
Early detection of aspirin overdose treated with activated charcoal to decrease aspirin absorption. Why?
Charcoal has pores that allow drug molecules to be attached to activated charcoal. AC is not absorbed and will be excreted or removed through faeces -> decreasing absorption of aspirin
Transporters in
Intestine (absorb)
Liver (metabolise)
Kidney (excretion)
or
Organs with barrier function
- brain - placenta
Placenta transporters-whatdo they do
protect fetus or developing embryo from harmful symbiotic like alcohol
MDR1
(multidrug resistance protein 1) or P-gp (P-glycoprotein)
MRP2
(multidrug resistance-associated protein 2)
BCRP
(breast cancer resistance protein)
3 types of ATP binding cassette transporters
MDR1
MRP2
BCRP
In Vitro predict oral absorption with which cells
Caco-2 cells
Caco-2 Cells
- og derived from a human colon adenocarcinoma
- an in vitro system to predict intestinal permeability and efflux liability
- grow as a monolayer and differentiate on reaching confluence into intestinal epithelial cells
- express multiple key drug transporters, including MDR1, BCRP and MRP2
Apical membrane
the surface of an epithelial cell that faces a lumen, such as that of the intestines
Basolateral Membrane
faces the interstitial fluid and is indirectly in contact with the blood
Bidirectional Transport Assays
2 ways through the apical chamber or basolateral chamber
A: add drug to A chamber > measure drug conc by taking sample from B chamber at defined time points > calc apparent permeability P (app(A-B))
B: add drug to B chamber > measure drug conc by taking sample from A chamber at defined time points > calc apparent permeability P(app(B-A))
Impact on oral bioavailability of a drug
(i) transporter knockout (KO) Caco-2 cell lines
(ii) cells transfected with transporter of interest
(iii) inhibitor of transporter of interest
check slides
- drug-drug interaction (DDI)
co-administration of drugs that act as a substrate/an inhibitor/an inducer of efflux transporters
