Physiochemical Drug Properties: Kunze

Question 1

Physicochemical Properties and Drug Disposition

Answer 1

• ADME=drug ability to diffuse through a membrane
• Only uncharged through membrane with simple diffusion
  
  • Structure→Charge→Charge at different pH
• Charged through membrane with efflux transporter
  
  • amino acid (zwitterionic), sugar (polar)

Question 2

Absorption

Answer 2

• Dissolution, charge, lipophilicity and transporter
• Apical/basolateral membranes have very different transporters

Question 3

Distribution

Answer 3

• Extracellular and Intracellular drug targets
• May need to go through additional barriers
  
  • Cytoplasmic membrane, nuclear membrane, BBB

Question 4

Metabolism

Answer 4

• Enzymes that metabolize/activate prodrugs in hepatocytes
• Generally make more polar and less active so that if is excreted
• Determines how long drug lasts in body
• Controls systemic bioavailability of drug

Question 5

Excretion

Answer 5

• Kidneys: metabolites and unchanged drug
• Renal clearance depends on amount reabsorbed from filtrate
  
  • drug ionized state in tubule
  • Biliary excretion via transporters located on the cannicular membranes of hepatocytes
• Lipophilic; retained in kidney; easily absorbed and retained in body.

Question 6

Ionization State of Drug

Answer 6

• pH 7.4 is neutral
• Often pH gradients across membranes
  
  • Determines concentration of drug on each site and the direction of movement of solute

Question 7

Here are the pH values for various fluids.

Answer 7

Blood: 7.4

Urine: 5-8

GI: 1-7

CSF: 7.3

Question 8

Henderson Hasselbach and Rearrangement

Answer 8

• pKa=pH-log(conjugate base/conjugate acid)
• (conjugate base/conjugate acid)=10^(pH-pKa)

Question 9

Carboxylic Acid Example:

Answer 9

• pKa=4.2
• At neutral pH, mostly negatively charged
  
  • Penetration into tissues depends on logP of neutral conjugate acid because negatively charged in the blood
  • Bound to blood plasma proteins and have high unbound volumes of distribution
  • Half neutral at pH 4.2 and absorbed in duodenum
• If other ionizable groups are present, could become zwitterionic and not be able to pass without a transporter
  
  • Many drugs zwitterionic because of critical binding interactions to targets

Question 10

Aromatic Amine Example:

Answer 10

• pKa=4.6
• Conjugate acid is charged (anilinium ion), base (aniline) is neutral
• Absorbed better in distal (more basic) regions of GI tract
• logP less problematic to absorption and distribution since the neutral form usually predominates

Question 11

Aliphatic Amine Example:

Answer 11

• pKa=10
• Neuroactive compounds
• Like to go through membranes
• Lower pH favors the charged conjugate acid
• Still get amines in at the “nil” percent because of lipophilicity
• Lipophilicity is something that has to be looked up. You’ll build an intuition about it.

Question 12

Ciprofloxacin

Answer 12

• 3 ionizable groups
  
  • Carboxylic acid (pKa: 4.5), aliphatic amine (pKa: 9-10), aromatic amine (pKa: 4.5)
• At pH 7: aniline neutral, aliphatic charge, amine neutral
  
  • Bears at least one charge in range of pH 2-9 and will not pass through membranes
  • However absorbed from GI tract due to uptake transporters
• Bioavailability limited (60%)
• Amino acids need transporters to get through membranes
  
  • Can stick amino acid group onto drug to get it through a membrane

Question 13

Fluoxetine

Answer 13

• CYP2D6, polymorphisms, 10% are poor metabolizers
• Positive at neutral pH
• Goes through membranes because of lipophilicity and in equilibrium with neutral species
• M1-M5 muscarinic receptors

Question 14

Answer 14

4.6

Question 15

Answer 15

4.8

Question 16

Answer 16

pka=4.2

Question 17

Answer 17

9.6

Question 18

Answer 18

10

Question 19

Answer 19

5.0

Question 20

Answer 20

7

Question 21

Answer 21

10

Question 22

pKa trends to note

Answer 22

• EWG lower pKa through resonance or induction
• Aliphatic and aromatic carboxylic acids have pKa ~4 and are always weak acids
• pKa for aromatic amine (3-5) are 6 pka units lower than aliphatic amine (8-10). Aromatic amine, imidazole, and pyridines are weak bases, aliphatic amine strong base
• Use integer pKa values
• Can pass through membrane if only 0.1% uncharged because lipophilicity of uncharged will contribute substantially.
• Systemic bioavailability can be hard to achieve
• When a membrane separates compartments with different pH’s, the unionized concentration in each compartment is the same but the ionized concentrations will differ

Question 23

LogP

Answer 23

• Solubility of unionized drug in octanol
• logP=log[octonal]/[water]
• Most drugs have positive log P (like to be in membrane); log P of 0 means equally in both parts
• Independent of pH

Question 24

LogD

Answer 24

• Total drug in each phase
• Non-ionizable drugs: Log P and Log D are the same
• Log D for weak acids (conjugate acid is neutral) decreases as pH increases
• Log D for weak bases (conjugate acid is charged) increases as pH increases
• Log D is pH dependent
• pKa, log P, and log D are all related so that if you know 2 values you can calculate the 3rd value

Question 25

Beta Blocker Log P and Log D example:

Answer 25

* Have amine group (pKa=9); handle of the drug is what changes * Increased Log P and Log D means better absorption * % Absorbed does not equal % bioavailable because of first pass metabolism * % Excreted unchanged is inversely related to Log P and Log D * Too high of lipophilicity can be bad * Highly lipophilic (log p\> 5) are readily absorbed * Partition into lipid compartment * Large volumes of distribution * Long half-lives (difficult to dose) * Persist in the brain

Question 26

Lipinski’s Rules:

Answer 26

* Predict ADME, but not pharmacologic activity (receptor binding) * An orally active drug can have no more than one violation of criteria * No more than 5 H-bond donors * No more than 10 H-bond acceptors * MW \< 500 g/mol * Log P no greater than 5

Question 27

Warfarin, Ritonovir and Lipinski's rules

Answer 27

* Warfarin meets them and is absorbed * RTV doesn't meet the rules but it also absorbed * Lipinski is for ORALLY absorbed (not IV)