Lecture 3 Flashcards
Biopharmaceutical Properties of Drugs
Medicinal Chemistry
Studies how chemical structure influences biological activities. An interdisciplinary science at the intersection of organic chemistry, biochemistry, structural biology, computational chemistry, molecular biology, and physical chemistry.
Physicochemical Properties
Properties derives from how functional groups influences its acid-base properties, water solubility, partition coefficient, stereochemistry, and ability to interact with biological systems/targets, such as enzyme active sites and receptor sites.
Biopharmaceutical Properties
Properties derrived from how physicochemical determine biological action of pharmaceuticals. Examples include solubility, partition coefficient, and degree of ionization, which are in turn determined by chemical structure and stereochemistry of the drug.
Routes of Administration
- Choice of administration route in a given situation depends on drug and patient related factors
- Can be local or systemic
- In systemic applications, the drug is absorbed by the blood and taken all over the body
Examples of routes of administration: oral, SL, rectal, epithelial, inhalation, parenteral
Passive Diffusion Steps
- Drug in formulation
- Drug goes through dissolution
- Drug in solution
- Drug is absorbed across a barrier (ex: cell membrane)
- Drug in blood
Most drugs are absorbed via this route
How do physicochemical properties connect to med chem?
- Drug must overcome many hurdles to reach its target
- Different routes have different hurdles
- Many complication biological processes can be modeled using simply physical chemistry models or processes (can increase optimization)
3 Drug Permeation Methods
- Passive Diffusion
- Carrier-Mediated/Active Transport
- Convective Absorption
Passive Diffusion
- Most drugs diffuse via this route
- Net movement is from high concentration to low (with concentration gradient)
- Energy not required
- Related to lipid solubility (partition coefficient)
- Hydrophobic molecules can “partition” into membranes which can be measured to find coefficient P
Partition Coefficient
P = Co/Cw Co = drug concentration in oil phase (octanol) Cw = drug concentration in water
-As P increases, the lipid solubility increases (easier to cross membrane and be absorbed)
Since range of values can vary so widely, often use log(P)
Why Octanol?
- Contains 8 carbons and one hydroxyl group
- May closest mimic the bell membrane
- Gives the best correlation to actual in vivo values
Lipid Solubility
- Function of combination of effects for all functional groups
- General rule: as the number of carbons and hydrogens increases, the log(P) increases (longer the hydrocarbon chain, the more lipophilic the molecule)
Increase in log(P) correlates to…. (8)
- Increased absorbed percentage of unionized drug
- Increased clotting ability
- Increased receptor affinity (binding)
- Decreased aqueous solubility
- Increased binding to P450 enzymes
- Increased absorption through membranes
- Increased binding to blood and tissue (less drug available)
- Increased binding to hERG heart ion channel (increased cardiovascular toxicity)
NOT ALL OF THESE ARE DESIRABLE, MUST OPTIMIZE log(P)
Methods to Alter Lipophilicity (5)
- Replacing hydrogen with a halogen increases lipophilicity
- Replacing hydrogen with hydroxyl decreases lipophilicity
- Removing quinoline N to give carbocyclic ring greatily increases lipophilicity (only slightly offset by the inclusion of an ether)
- Addition of an oxygen into ring next to nitrogen increases lipophilicity
- Replacement of quinoline with aromatic ring increases lipophilicity (further enhanced by addition of trifluoromethyl group)
Distribution Coefficient
- If compound can ionize, the partitioning of compound between water and octanol will be pH dependent
- Ionized portions will stay in aqueous solution, neutral portions will pass membrane (an octanol)
Distribution Coefficient Equations
Acid: D = [HA]octanol/([HA}aq + [A-]aq)
Base: D = [B]octanol/([BH+]aq + [B]aq)
-Effective lipophilicity of ocmpound at given pH is a function of both lipophilicity of unionized compound and the degree of ionization
