Exam 3 Flashcards
Partition Coefficient
Ratio of concentrations in two immiscible solvents (eg octanol and water); K(o/w)=COctanol/CWater
pH-partition hypothesis
For drugs absorbed by a passive, transcellular mechanism; permeability transport depends on the fraction of unionized drug at the intestinal pH
Solubility and partition coefficient
in general as ko/w increases, solubility decreases
Solubility depends on
- molecular structure
- physical state (solid, liquid)
- composition of solvents (types, co-solvent perentages, solution components, pH/temperature)
- measurement methods (equilibration time, detection method)
Physicochemical properties of the drug that affects absoprtion
- solubility
- drug stability in solution
- lipophilicity
- molecular size and shape
- pka of the ionizable groups
- physical state of the drug (amorphous vs. crystalline, polymorphism, hydrates/solvates,liquid/gaseous)
***Factors governing drug performance in the clinic
- physicochemical properties of the API
- physicochemical properties and the composition of the formulation
- physiological barriers that influence the “targeted bioavailability” of the drug
Performance
- the ability of the drug to elicit a therapeutic response
- the ability of the drug to stay in a safe therapeutic range during the dosing regimens
- a lack of a toxic or non-efficacious response
- described by both pharmacokinetics and pharmacodynamic processes
- it is a function of the drug, the formulation and the body - it can be a moving target
Druggable protein
proteins that can bind drug-like compounds with binding affinity below 10mM (it is inferred that the compound must be able to functionally modulate the protein)
Gene
druggable genees are identified by pharmacogenomic methods
protein
genes that encode disease-related proteins that can be modulated by drug-like molecules are identified
pharmacophore
druggable genes are converted to proteins using in silico methods and binding cavities can be identified
Druggability Stages
- discovery stage
- assesses the ability of NCEs to bind to the drug target
- in this stage, in vivo models are used to assess
Developability
- refers drug product performance
- incorporates factors like biorelevant solubility and dissolution
- formulation factors releated to ADME/T incorporated
Overcoming the effects of the pH Partition Hypothesis
- functionalize the compound-change pKa
- prodrug strategy (modify the charged moiety, modify the molecule to be recognized by a transporter)
- salt selection (ion pairing effective in improving permeation, salt form can alter unionized fraction)
- drug delivery system
Formulation design requires a consideration of:
- Physicochemical properties of the drug
- physicochemical properties and composition of the formulation
- biological factors that influence performance (ADME and toxicity; ADMET)
Formulation design requires a consideration of:
- Physicochemical properties of the drug
- physicochemical properties and composition of the formulation
- biological factors that influence performance (ADME and toxicity; ADMET)
Formulation Factors Affecting Absorption
- Dosage Form design (size, excipient compositions, etc/manufacturing parameters brief discussion)
- Rates of drug release from the dosage form (disintegration, dissolution, deaggregation, erosion of coatings, osmotic pumps)
- Residence time at absorption site (mucoadhesives, coatings)
What are excipients?
- usually inert substance that forms a vehicle
- substances added to therapeutically active compounds to improve appearance, bioavailability, stability, and palatability of the product
Excipients…
- are not inert
- US warning on HIV excipient
- Glaxo Wellcome’s protease inhibitor (Agenerase) is warned to be dangerous due to the amount of propylene glycol in solution
13 Functional classes (IPEC - America)
- Binders
- Disintegrants
- Fillers (Diluents)
- Lubricants
- Glidants (flow enhancers)
- Compression aids
- Colors
- Sweeteners
- Preservatives
- Dispersing Agents
- Film formers
- Flavors
- Printing Inks
Common Excipients
- Cellulose based (microcrystalline cellulose)
- sugars (sucrose, lactose, mannitol)
- Starch
- synthetic polymers
- Inorganic
- Magnesium stearate
Critical Factors
- origin, source and availability
- functional catergory
- quality and purity
- impurity levels and extent of characterization
- batch-to-batch consistency
- stability in the pure form and in formulation
- compatibility with active and packaging material
- toxicological considerations
- cost, regulatory or compendial status
- biological activity, if any
- patent status
Common Methods for Excipient Compatability Testing
- Binary or formulation blends
- Binary or formulation blends with 10 - 20% w/w water
- Suspension or solution of excipients and drug
- Mechanical stress by milling or co-milling drug
- Using amorphous drug
- Compacts of prototype formulation by direct compression
- Tablets processed by wet granulation
- Calorimetry
Flow Properties - Angle of Repose
- excipients can be used to control flow-glidants
- better flow means better mixing and filling
- increases ability to keep dose the same
- the angle of repose is a characteristic of how well a powder flows
- SMALLER ANGLE = INCREASED FLOW
Organoleptic Senses to consider when coating/binding (clinical trials) treatments
- sight (size, color, shape, markings)
- smell
- sound (tablet/pellet inside a capsule)
- taste
- touch
Those affecting bioavailability, stability, and marketing considerations
- disintegrants-enhance rate of disintegration/dissolution
- coatings-control release
- flavors/sweeteners-mark drug taste
- colors-recognition
- miscellaneous ingredients
Physiological Factors Affecting Absorption
- absorbing surface area
- residence time at absorption site
- pH changes in lumen
- permeability/perfusion (functional and molecular characteristics of transporter and metabolism)
- dietary fluctuations/effects
- complexation/protein binding
- biliary uptake and clearance
Epithelia
- predominantly used for external surfaces although endothelial cells are epitheliod (sit on a layer of extracellular matrix proteins; epithelial cells are polarized with directional transport)
- there are several different types
- endothelial cells line the inside surfaces of body cavities, blood vessels and lymph - they have simple squamous morphology. Endo = in, therefpre internal surfaces
Simple squamous types
- thin layer of flattened cells that are relatively permeable
- lines most blood vessels
- placenta, endothelial cells (?)
Simple columnar types
usually found in the GI tract
Translational types
comprised of several layers with different shapes - usually required to stretch
Stratified squamous types
multiple layers of squamous cells that cover areas subject to wear and tear - skin is one type that the barrier function comes from keratinization
Composition of biological membranes
- all living cells are enclosed by one or more membranes, which define the cell as the living unit
- the membrane isolates the cellular contents from the environment - forms a barrier
- the cell membrane is a semi-permeable membrane, permitting the rapid passage of some chemicals while retarding or preventing the passage of others
- cellular lipid composition is polarized and intracellular membrane lipids are different than extracellular lipids
Does cholesterol only have harmful effect on membranes
No, it provides fluidity at lower levels. Actually, when it exceeds a certain level in a membrane, the membrane undergoes a phase transition and forms a liquid crystalline state.
We call this hardening atherosclerosis when it occurs in the vasculature.
Tight Junctions
- important for the function of the confluent epi-/endothelia
- restrict solute movement between the cells (paracellular)
- polarize cells into apical (luminal - blood facing) and basolateral (abluminal - brain facing) areas
- allow for differing functions between the two membranes
- TJs can involve up to 50 proteins
Cell-Based Assays
Look up equations.
Intestinal Transport Mechanisms
- Passive (non-saturable)
- **paracellular (between cells)
- **Transcellular (through cells)
- Carrier-Mediated (saturable)
- **active (energy dependent)
- **facilitated diffusion (energy independent)
General Interpretation of Caco-2 vs. PAMPA Data
See chart.
Drug transporters
Drug transporters are membrane-bound proteins widely distributed throughout the body, prominently on apical and basolateral surfaces of organs involved in clearance
Physiological role of these transporters is to move important molecules across membranes; this capacity includes moving drug molecules across membranes
Drug transporters are a crucial determinant of tissue and cellular distribution of drugs, not only for drug clearance but also sanctuary organs
Variations in drug transporter activity can be major determinants of drug response and drug safety
This has primarily been identified in adults with much less data in children
Solute Carrier (SLC)
43 Subfamilies
> 300 members identified
Generally influx or secretory efflux transporters
PepT1, OATs, OATPs
ATP-Binding Cassette (ABC)
7 Subfamilies
50 members presently identified
Generally efflux- multidrug resistant transporters
P-glycoprotein, MRPs
Absorption
Refer to diagram.
Conventional Terminology: Influx Transporters
Transfer substrates into cells
Conventional Terminology: Efflux Transporters
pump substrates out of cells