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What are the players in drug delivery?
- Dosage form
- Absorption organ
- Target Organ
- Target Cell
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What is the ophthalmic route of administration?
Eye
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What is the site of auricular/otic drug delivery?
Ear
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What phase is the lipid bilayer?
Fluid
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What are the types of Carrier mediated movement across membranes?
- Facilitated diffusion
- Active transport
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What is another term for vesicular mediated transport?
Phagocytosis
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What are the types of Passive transport?
- Around cells
- Diffusion though membranes
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What would you expect from a Vmax/Concentration plot of an actively transported molecule?
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What would you expect from a Vmax/Concentration plot of an passively transported molecule?
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What is the long term for ABC transporters?
ATP binding cassette transporters
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What do ABC transporters do?
- Aid in movement across the membrane
- RNA translation
- DNA repair
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Describe the composition and location of ABC transporters:
Membrane proteins
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What health related activities are ABC transporters involved in?
- Cystic fibrosis and other diseases
- Tumor resistance
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What are the drug substrates for Amino acid transporters?
- Baclofen
- Cyclosporin
- L-dopa
- Gabapentin
- methyldopa
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What are the drug substrates for Peptide transporters?
- b-lactam antibiotics
- ACE inhibitors
- methyldopa
- Cyclosporins
- Cephalexins
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What two transporters are peptide transporters?
hPEPT1 and HPT1
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What two transporters are nucleoside transporters?
CNT1 and 2
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What three transporters are organic anion transporters?
OATP1, 3, and 8
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What three transporters are Organic cation transporters?
OCT1 and OCT2
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What two transporters are Bile acid transporters?
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What are the drug substrates for Nuscleoside transporters?
- Zidovudine
- Zalcitabine
- dupyridamole
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What are the drug substrates for Organic anion transporters?
- Ceftriaxoine
- Benzoic Acid
- Mthotrexate
- Pravastatin
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What are the drug substrates for Organic cation transporters?
- Thiamine
- Desipramine
- Quinidine
- Midazolam
- verapamil
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What are the drug substrates for Bile acid transporters?
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What law describes passive movement across a membrane?
Fick's law
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What is diffusion?
Process of mass molecular transfer due to random molecular motion and a concentration gradient
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What is the driving force for diffusion?
Concentration gradient
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What pharmaceutical examples were given for diffusion?
- Transport of drugs through a polymeric membrane
- Percutaneous absorption
- GI absorption of a drug
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What is a Barrier in terms of diffusion?
An area of resistance to diffusion
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What is a Membrane?
A solid or semisolid sheet that separates and regulates phases or materials passing through it.
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What is Flux (J)?
The amount of material moving through a cross-sectional area over time.
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What is Fick's Law used to measure?
Flux
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What is proportional to?
The concentration gradient
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Is the diffusion coefficient a constant?
No
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Does the diffusion coefficient stay the same for a given product?
- No, changes with:
- Temperature
- Concentration
- Solvent properties
- Chemical nature of the diffusant
- Pressure
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Summarize Fick's first law:
The Flux is proportional to the Concentration gradient
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Summarize Fick's second Law:
The rate of change in a concentration gradient within the diffusional field is proportional to the rate of change in the conc. gradient at the point in the field
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What law would you use to describe diffusion through anisotropic membrane?
Fick's first law
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What is isotropic?
Not varying in magnitude
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What are the assumptions of Diffusion through isotropic membranes?
- Quasi steady state
- No aqueous boundary layer exists
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Describe graph of release vs Time of a drug diffusing through an isotropic membrane:
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Non-linear at first
Later becomes constantly linear
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What is the Lag time in terms of the graph:
The point of interaction for the extrapolated steady state portion of the curve
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What is the lag time in terms of the movement of the diffusant?
The time for the penetrant to establish a uniform concentration gradient
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What is a transporter that moves substances out of the cell?
Efflux transporter
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What type of transporter moves substances into the cell?
Uptake transporter
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What are the critical factors in influencing whether a transporter is creating efflux or uptake?
The orientation and location in the cell
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Describe the rate of drug uptake of a carrier mediated drug:
Fastest at the beginning, slows and eventually plateaus
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Describe the rate of transport of a drug that moves by passive diffusion:
Steady state of flux (linear)
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Are there more transporters on the Apical (lumen side) of the epithelial GI cells or the basolateral side?
The Lumen side
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Where is P-gp located within the cell?
Apical membrane
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Where is P-gp located within the body?
GI, Liver, Kidneys, Blood Brain Barrier
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The action (efflux or uptake) of PGP is what?
Depends on the location in the membrane and cell
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What is P-gp?
Transporter called P-Glycoprotein
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What Drug properties are important when considering transportation (7)?
- Size
- Polarity
- Charge
- Diffusion
- Facilitated diffusion
- Administration (IV vs Oral)
- Competitive binding
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What transporter factors contribute to drug movements?
Location on apical or basolateral surface (Uptake vs. Efflux)
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What family of transporters does P-Glycoprotein belong to?
- ABC transporters
- Encoded for by MDR1
- Efflux pump
- Apical epithelial cell expression
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What therapies does P-gp effect?
Chemotherapies and others
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Why is P-gp so important?
It expels drugs
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What is a P-gp substrate?
A drug that is expelled by P-gp
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What considerations are applicable to P-gp substrates?
Need to consider the route of administration (GI especially tough)
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Describe the basic characteristics of a P-gp substrate:
- MW = 250-1200
- Usually lipophilic
- Usually basic or uncharged
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Describe the significance of Loperamide and P-gp:
- Loperamide is an m-opioid receptor antagonist which could have analgesia, sedation, etc. (systemic effects)
- Does not have any systemic effects, only GI
- Is a P-gp substrate that is expelled in the GI
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If Loperamide is administered PO, what effects does it have?
Anti-diarrheal
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What drug can elevate the effects and allow Loperamide to enter the CNS?
Quinidine
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What would a patient experience if quinidine were administered with loperamide?
Increased anti-diarrheal effects and increased CNS effects
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What is quinidine?
Potent P-gp inhibitor
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The majority of drug movement happens through what process?
Passive mechanisms
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What are the critical parameters of drug movement?
- Concentration gradient
- Rate constants
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What is pharmacodynamics?
What the drug does to the body
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What is Pharmacokinetics?
What the body does to the drug
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