Physiological barriers to drug discovery Flashcards
Coatings
-control diffusion rates
-modify release properties
disintegrants
control regions of release
Lubricants
slow dissolution
Internal excipients
-swellable and nonswellable matrices
-inert plastics
Coating goals
-protection
-mask taste
-release
-aesthetics
-prevent inadvertent contact with drug
Aqueous film coatings contain
-film-forming polymer
-plasticizer (flexibility/elasticity)
-colorant and opafier
-vehicle
Non-aqueous film coatings contain
-film-forming polymer
-alloying substance (for solubility)
-plasticizer
-surfactants (film coat spreading)
-colorant and opafier (aesthetic)
-flavors
-glossant (luster)
-volatile solvent (spreading/evap)
Enteric coatings
-added to prevent early release of API in a region where it may undergo chemical breakdown
Reasons for enteric coating
-protect API from gastric fluids
-prevent gastric distress from API
-target delivery to an intestinal site
-delayed release
-deliver in higher local concentration
sustained release
-slow release
-delay onset of action but effect is sustained
Controlled release
-sustained but with reproducibility/predictability in drug release kinetics
-allows us to maintain a narrow drug plasma concentration-steady state
Controlled release fromulations
-coated beads, granules, microspheres
-multitablet system
-microencapsulated
-drug embedding in slowly eroding matrix
coated beads, granules, microspheres
-release by programmed erosion
-contacts
multitablet system
small tablets in a gelatin capsule
microencapsulated
-into walled material that allows spreading of particles across absorbing surface
Drug embedding in a slowly eroding or hydrophilic matrix
-drug homogenously dispersed in the eroding matrix
-release controlled by erosion rate
Steady state
rate going into body must equal the disposition
Drugs best suited for oral controlled release form
-exhibit neither slow nor fast rates of absorption/excretion
-uniformly absorbed from gas tract
-relatively small doses
-good therapeutic window
-chronic therapies better suited than acute
Factors of absorption: Permeability
functional and molecular characteristics of transporters and metabolism
epithelia
-line most external surfaces but does include endothelial cells
-sit on layer of extracellular matrix proteins (basal lamina)
simple squamous epithelia
-thin, flat layer
-pretty permeable
-lines most blood vessels, placenta
simple columnar epithelia
usually in GI tract
translational epithelia
-several layers with dif shapes
-usually need to stretch
Stratified squamous epithelia
-multiple layers of squamous cells that cover wear and tear areas like skin
Endothelial cells
line inside surfaces of body cavities, blood vessels, lymph
-simple squamous
Cell membrane
-semi-permeable
-lipid composition is POLARIZED, and intracellular membrane lipids different from extracellular
Cholesterol in membranes
-provides fluidity at low levels
-too much can cause phase transition
atherosclerosis
hardening of membrane from liquid to crystalline state because of cholesterol in the vascular system
Permeability coefficient: used in membrane and cell-based assays
Papp = (dQ/dt) / ACo60 cmsec^(-1)
dQ/dt= amt of compund appearing on receiver side as function of time
A=surface area of filter support
Co=initial concentratioin of compound apllied to donor side
1/Papp = (1/PM)+(1/PABLFC)
PAMPA sandwich system for permeability assays
-donor and acceptor plates (sandwich)
-acceptor wells (pH buffer + surfactant)
-donor wells (pH buffer + sample)
-membrane sandwiched between acceptor and donor well (plates)
Lipid composition
-vary according to organ
-high in blood brain barrier
-changes influence absorption and function of cells
Transport mechanisms
-passive (non-saturable)
-carrier-mediated (saturable)
Passive (non-saturable) transport
-paracellular
-transcellular
=through and between cells
-Fick’s first Law idk prob doesnt matter
carrier-mediated (saturable)
-active (energy dependent)
-facilitated diffusion (energy independent)
paracellular transport
-hydrophobicity
-size and shape
-pKa
transcellular transport
-lipophilicity (hydrophobicity)(H bond potential)
-size and shape
-pKa
Typical Permeability Assays
-PAMPA: passive, during exploratory
-Caco-2: passive, active, paracellular, during development
-both: mech info, during discovery and pre development
Caco-2 vs PAMPA permeability graph
y=x
-slope=passive diffusion
-top left half is ABSORPTIVE influx/uptake and/or paracellular transport
-bottom right half is SECRETORY and efflux transport, metabolism
Permeability deviations
-some hindered due to drug resistance/secretory transporters (efflux)
-some enhanced by absorptive influx permeability
Drug Transporters
-membrane bound proteins
-move molecules across membranes
-determinant of tissue and cellular distribution of drugs
-variations in transporter activity can affect drug response
Nutrient and Xenobiotic transporter types
-SLC
-ABC
Nutrient and Xenobiotic transporters nomenclature
transporter type; family number; species variant
ex: PepT1 –> SLC 15 A1
*no spaces just wanted to show breakdown
Solute carrier (SLC)
-43 subfamilies
->300 identified
-generally infux or secretory efflux transporters
-PepT1, OATs, OATPs
ATP-binding Cassette (ABC)
-7 subfamilies
-50 members
-generally efflux-multidrug resistant transporters
-P-glycoprotein, MRPs
Absorption routes of permeability
A. Influx transporter mediated (through)
B. passive transcellular (through)
C. passive transcellular and efflux (through then out)
D. Passive paracellular (between)
E. metabolism (inside)
F. Efflux of metabolites (out)
Influx transporters
substrates INTO cells
Efflux transporters
substrates OUT of cells
Absorptive transporters
substrates into blood circulation
Secretory transporters
substrates from blood into bile, urine, GI lumen
Permeability barrier
Pbarrier = Ppara + Ppassive transport + P active1transport + P activeNtransport
-efflux and metabolism give negative values
Passive Paracellular Permeation (Ppara)
-linear increase in permebility with increasing concentration
-adjuvants can open tight junctions and increase transport
Passive transcellular permeation
-permeability increase with concentration increase
-dissolution/solubility limited with high lipophilicity
Facilitated/Active transcellular permeation
-affinity (KM), capacity (Vmax)
-concentration dependent saturation
-expression level (constitutive, induced)
-function (interactions, inhibition)
-excipients can limit effects of efflux by Pgp or BCRP
