Lecture 4 Flashcards
What is BCS class 1? What is the dose approach?
High S and high P
Simple solid oral dosage form
What is BCS class 2? What is the oral dosage form?
Low S and high P
Increase SA, like particle size reduction, solid solution, solid dispersion
Use surfactants
What is BCS class 3? What is the dosage form approach?
High S and low P
Incorporate permeability enchancers, max local luminal concentration
What is BCS class 4? Oral dose approach?
Low P and S
Increase SA, particles size reduction, solid solution solid dispersions, use surfactants, incorporate enchances and max luminal concentration
A drug is only effaciouis if it ____ to its target in the ___?
___ measures the amount of active ingredient that will end up in blood stream?
Distributes, appropriate tissues
Bioavailability
What is bioavailability?
Ratio of AUC for the drug given by a non IV route to the AUC of same drug given IV (always higher)
-Fabs= 100 AUC po *Div/AUCiv *Dpo
What is the first pass effect?
When a drug after being absorbed from GI passes thru the liver via portal vein before reaching system circulation
—gets rid of the drug a lot
What is Lipiński rule of 5?
Good bioavailability orally if:
MW < 500 g/mol
Log P<5 (measure lipophilicity, dissolves in fat instead of water )
HBA < 10
HBD <5
RB<10 (rotatable bond, sp3 bonds)
PSA<140 A
primarily small molecules and synthetic molecules
Example of natural product that still works?
Paclitaxel
—still used in drug discovery, and in lung cancer
—has high target affinity allows it to get across the membrane
What is not permeability across lipid membranes?
What estimates passive permeability ?
What does PAMPA show?
Charged species
Parallel artificial membrane permeability assay (PAMPA)
drug becomes less and less permeable when it becomes charged , depends on PKA and PH of drug and environment **
Shows how much of drug is in the membrane—> measured by HPLC-MS
What are CACO2 cells?
What does CACO2 show that PAMPA does not?
Are CACO2 cells heterogeneous?
Derived from colorectral carcinoma
Active and passive ways drug is transported into and effluxed (Actively) out of the intestinal epithelium to reduce abosorption
shows more realistic
* uses efflux pumps
Yes, so comparing data from sources is challenging
Active vs passive transport?
Active: against conc gradient, with transporters, uses energy
Passive transport: down concentration gradient
Molecules with _____ and ___ in vitro (SPR, FRET) show___
What is this discrepancy called?
High affinity and activity
- reduced or no activity in cell based assays
Cell shift
What are factors affect cell shift?
Permeability—- molecule cannot cross cell membrane
Metabolism—- rapid metabolic degradable or modification
Non selective protein binding: binding to unintended intracellular proteins reduces target engagement
Target upregulation : altered expression of the intended target in cellular environment
What is clearance? What is half life?
Drugs are removed from the body, thru metabolism and excretion
Time required for drug concentration to decrease by half —> 1/2=0.693*Vd/CL
What enzymes are vital for metabolism of drugs?
Cytochromes P450
What’s s unbound clearance?
Only free drugs are available for metabolism or excretion
Bound drugs cannot be metabolized
What’s is renal clearance?
Equation?
Blood flows thru kidneys and compounds are filtered out to the urine (CL renal) or remain in the blood
Csys =Cl hepatic + Cl renal
What’s phase 1 metabolism?
What are the reactions?
What is the catalyst?
Introduces or exposes functional groups on the drug molecule to make it more reactive for phase 2 metabolism
-oxidation, reduction, hydrolysis
-iro-oxo species within heme is the catalyst—> attract CH bond
What is CYP3A4 and CYP2D6?
Responsible for metabolizing 50% of drugs
Polymorphic drug metabolism (codeine to morphine)
What is phase 2 metabolism?
What explains the reason to why people respond differently to the same drug?
Adds large polar groups to make the drug more water soluble for excretion
Enzymes variability in CYP2d6
What can be used to assay oxidative metabolism? What is it helpful for?
Liver microsomes
Helpful to understand where metabolic hotspots may exist
What is oxidative metabolism referred to as?
What does terfenadine do?
Phase 1
Blocks hERG, an important ion channel in the heart, leading to toxicity—> replaced with fexofenadine
What gives both phase 1 and phase 2 metabolism?
What does hepatocyte incubation ?
Hepatocytes
Phase 2 conjugation
What are mechanism of renal clearance?
Filtration: passive where unbound drugs are filtered from blood—> urine
Secretion: active transport to secrete drug from blood to urine
Reabsorption: some drugs can be reabsorbed back into the bloodstream
