17- sar part 3 lipinski

Question 1

explain when an acid is lipid soluble and water soluble? vice versa?

Answer 1

Ionized = water soluble, lipid insoluble
Neutral = water insoluble, lipid soluble

Question 2

explain when a base is lipid soluble and water soluble? vice versa?

Answer 2

ionized = lipid insoluble, water soluble
neutral = water insoluble, lipid soluble

Question 3

where do the drugs pass once in the blood?

Answer 3

• drugs must pass the liver
• Liver is designed to “detoxify” our food
• Foreign molecules are metabolized to be removed from blood
• Hydrophobic molecules are highly metabolized

Question 4

what are the two phases of metabolism in the liver?

Answer 4

• Phase I: oxidation

- Phase II: conjugation

Question 5

how are drugs transported to the body by blood?

Answer 5

• Lipophilic molecules bind to carrier proteins in the blood
  
  • Plasma protein binding
• Blood contains hydrolytic enzymes (cut large molecules into small ones)
  
  • Esterases
  • Proteases

Question 6

what body part clears substances from the blood?

Answer 6

• kidney
• Hydrophilic compounds are easily cleared from blood
• Hydrophobic molecules tend not to be cleared

Question 7

list the barriers to drug delivery for oral dosing

Answer 7

1. stomach (solubility water, stability, pH 2, enzymatic)
2. intestine (solubility water, stability, pH 3-8, enzymatic)
3. blood (permeability)
4. liver (metabolism, phase i, phase ii)
5. bloodstream (solubility water, protein binding, stability, enzymatic)
6. kidney (solubility water, permeability)
7. cells of the target organ (permeability)

Question 8

what are the properties measured and associated with ADME?

Answer 8

• Absorption
• Distribution
• Metabolism
• Excretion 💩

Question 9

what is the rule of 5

Answer 9

compounds that meet 2 or more of the following criteria are NOT likely to be well absorbed into the body

Question 10

what are rules

Answer 10

• more than 5 H bond donors
  
  • OH and NH
• more than 10 h bond accepters
  
  • N and O
• molecular weight greater than 500
• calculated LogP (CLogP) greater than 5
  
  • or measured LogP (MLogP) > 4.15

Question 11

what is the rationale for rule of 5 for Hydrogen bonds?

Answer 11

• H bonds increase water solubility
• H bonds make it difficult to cross lipophilic membranes
• too many H bonds makes it hard to cross lipophilic membranes

Question 12

what is the rationale for the rule of 5 for molecular weight?

Answer 12

• Large molecules tend to be less soluble
  
  • Create a larger cavity in solvents (water or lipids)
• Large molecules do not pass easily through tightly packed membrane lipids

Question 13

what is the rationale for the rule of 5 for LogP?

Answer 13

• Water solubility decreases as lipophilicity increases

- have to have balance between two things and has value of 5 as a cutoff

Question 14

why is lipophilicity important for drugs?

Answer 14

• Drugs must have a balance between lipophilicity and hydrophilicity (measured as equilibrium)
  
  • Dissolve in water (hydrophilicity)
  • Dissolve in lipid membranes (lipophilicity)

Question 15

list the equation for LogP

Answer 15

LogP = Log([Drugoctanol]/[Drug water])

• High number = lipophilic
• Low number = hydrophilic

Question 16

explain the difference between LogP and LogD

Answer 16

• have the same equation
• LogD is measured at pH 7.4
• LogD is between 1 and 3
• low number is good water solubility but low lipid bilayer permeability
• high number is low water solubility but high lipid bilayer permeability

Question 17

what are two common measurement methods

Answer 17

• Solutions (more accurate, if interested in putting into animals)
  
  • Make standard solution in water
  • Add equal volume of octanol
  • Shake
  • Separate layers and measure amount of drug in one of the layers
• HPLC (high performance liquid chromatography) (faster, for routine work)
  
  • Run sample through special HPLC column
  • Retention time used to calculate LogP

Question 18

what are the advantages and disadvantages of LogP?

Answer 18

• Advantages
  
  • Methods well established (FDA, courts)
  • Correlates well to Rule of Five
• Disadvantages
  
  • Each molecule requires different buffer
    
    • Must measure when molecule is in neutral form
  • Measurements not made at physiological conditions

Question 19

what are the advantages and disadvantages of LogD?

Answer 19

• Advantages
  
  • Methods well established
  • Easier to measure (fixed pH)
  • Correlates to Rule of Five
  • Physiological relevance (pH 7.4)
• Disadvantages
  
  • Less widely used than LogP (modern use only)