Physiochemical Properties of Drug Flashcards
Lipinski’s Rule: (The rule of 5)
There is poor absorption or permeation of a drug if the drug has these properties: (5)
> 5 H-bond donors > 10 H-bond acceptors > 500 Molecular weight > 500 Relative molecular mass > 5 log P (partition coefficient)
Veber’s rules: Poor bio availability of a drug when: (2)
> 140 A^2 polar surface area (PSA)
> 12 total H-bonds (HBD + HBA)
In general, as the number of H-bonds rises (greater polarity), partitioning into the cell lipid bilayer (rises) or (falls)? PSA is related to H-bonding
Falls
Higher MW and increasing size impedes —/— through the cell membrane. These properties also decrease — in the aqueous phase This makes the distribution of the drug to cell —. Other forms of transport include endocytosis (the membrane envelope is the more — molecule to help it across the membrane in a —) and — transport (directly through membrane- usually involves smaller, less — molecules). The ability of a drug to passively cross the cell membrane is modelled using values of —
passive diffusion solubility harder polar vesicle paracellular log-p
log-p values:
-1 –> 2: polar compounds, good — solubility, poor — solubility, poor absorption and —. They are excreted too
—.
2 –> 4.5: These compounds have Intermediate —, good balance between aqueous and lipid solubility. Good absorption + distribution. This is the log-p range for a lot of —.
4.5 –> 6: Non-polar compounds, poor — solubility, good — solubility, accumulate in environments rich in —.
They are excreted —
aqueous
lipid
distribution
quickly
polarity
medicines
aqueous
lipid
lipids
slowly
H-bonds must be broken for the drug to enter the —/—
Water solubility often increases with a lower —/—
Membrane bilayer
Molecular weight
For drugs needing to cross the BBB there is need to assist transport in (uptake) and slow or stop the — of drugs.
Transporters to enhance uptake: (4)
Name one drug exporter (1)
This drug exporter has – transmembrane segments in membrane bilayer. The drug attaches to 2 — binding regions which then become —, this induces conformational change which opens a pathway for drug to exit into the — fluid.
efflux PEP1 LAT1 MCT1 OATP1 Pgp 12 ATP hydrolysed extracellular
Development strategies to reduce efflux:
Exclude —. These deprotonate, the -ve charge interacts unfavourably with the -vely charges — headgroups which discourages transport.
Reduce number of — by adding a steric — or by replacing — atoms. Reduce HBA by adding adjacent — withdrawing groups. Modify — groups to raise —
Reduce the —/— and size to assist permeation through lipid membrane.
acids phospholipid HBD hindrance H e- Polar log-p molecular weight
Drug leads: A useful drug lead will have
3 3 300 60 3
