Physiochemical Drug Properties: Kunze Flashcards
1
Q
Physicochemical Properties and Drug Disposition
A
- 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)
2
Q
Absorption
A
- Dissolution, charge, lipophilicity and transporter
- Apical/basolateral membranes have very different transporters
3
Q
Distribution
A
- Extracellular and Intracellular drug targets
- May need to go through additional barriers
- Cytoplasmic membrane, nuclear membrane, BBB
4
Q
Metabolism
A
- 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
5
Q
Excretion
A
- 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.
6
Q
Ionization State of Drug
A
- pH 7.4 is neutral
- Often pH gradients across membranes
- Determines concentration of drug on each site and the direction of movement of solute
7
Q
Here are the pH values for various fluids.
A
Blood: 7.4
Urine: 5-8
GI: 1-7
CSF: 7.3
8
Q
Henderson Hasselbach and Rearrangement
A
- pKa=pH-log(conjugate base/conjugate acid)
- (conjugate base/conjugate acid)=10^(pH-pKa)
9
Q
Carboxylic Acid Example:
A
- 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
10
Q
Aromatic Amine Example:
A
- 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
11
Q
Aliphatic Amine Example:
A
- 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.
12
Q
Ciprofloxacin
A
- 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
13
Q
Fluoxetine
A
- 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
14
Q
A
4.6
15
Q
A
4.8
16
Q
A
pka=4.2
17
Q
A
9.6
18
Q
A
10
19
Q
A
5.0
20
Q
A
7
21
Q
A
10
