Drug Properties and Permeation

Molecular Size

the molecular weight or the size of a molecule, often expressed in daltons (Da or kDa). Most drugs are 200-500 Da . Smaller molecules generally cross membranes and distribute more readily

Solubility

The ability of a solute to dissolve in a solvent to form a homogenous solution. It depends on the nature of the solvent and solute (polarity), with "Like dissolves like" being a guiding principle

Water Soluble (Hydrophilic/Lipophobic)

Compounds that can dissolve in aqueous body fluids to distribute and reach their site of action. They are polar or ionic and associate with water molecules …. A degree of hydrophilicity is necessary for solubility in vivo3 .

Lipid Soluble (Lipophilic/Hydrophobic

Compounds that can readily pass through the lipid bilayer of cell membranes, crucial for absorption, distribution, and excretion (A, D, E)3 . Relative solubility in lipid vs. water is important for drug disposition

Topological Polar Surface Area (TPSA)

The contribution to the outer electron shell "surface area" sum of all polar atoms (primarily oxygen and nitrogen, including attached hydrogen atoms) in a molecule. It's a measure of a drug's polarity4 . An ideal TPSA for permeating cell membranes is 60-140 Ų, and for crossing the blood-brain barrier (BBB), it should be < 90 Ų

Log P (Octanol-water partition coefficient)

The logarithm of the ratio of a drug's concentration in an octanol phase to its concentration in an aqueous phase at equilibrium (Pow)5 …. It predicts the relative lipid solubility of a drug5 . "Drug-like" molecules usually have log P values between 0.5 and 5

Lipinski's Rule of 5

A set of guidelines predicting good oral bioavailability. Most oral drug molecules should have: log P ≤ 5, molecular weight ≤ 500 g/mol, number of hydrogen bond acceptors ≤ 10, and number of hydrogen bond donors ≤ 5 . Violating more than one of these rules may indicate problems with oral bioavailability .

Ionization

The process by which many drugs, which are weak acids or weak bases, can become charged (ionized) or uncharged (unionized) depending on the pH of the surrounding medium due to protonation or deprotonation

Unionized (uncharged) form of a drug

The form of a weak acid or base that can more readily permeate lipid membranes

Ionized (charged) form of a drug

The form of a weak acid or base that is typically more water-soluble and has difficulty crossing lipid membranes

Physical Barriers (to drug movement)

Anatomical structures in the body that limit drug distribution, such as the blood-brain barrier (BBB) and the placenta

Functional Barriers (to drug movement)

Transport proteins (efflux and uptake transporters) that can carry drugs into or out of cells, thereby influencing drug concentration in tissues and compartments12 .

Transport Systems

Mechanisms that facilitate drug movement across cell membranes. These include active transport (energy-dependent, uphill), passive diffusion (down the concentration gradient), facilitated diffusion (carrier-mediated, down the concentration gradient, not energy-dependent), and transcytosis (endo- and exo-cytosis

Efflux Transporters

Transport proteins, such as the MDR family of ABC proteins (e.g., P-glycoprotein), that pump drugs out of cells, lowering intracellular drug concentrations ….

Uptake Transporters

Transport proteins, such as organic anion transporters (OATs) and organic cation transporters (OCTs), that facilitate the movement of drugs into cells, increasing intracellular drug concentrations15 …

Polarization (of cells)

Refers to the uneven distribution of transporters on different membranes of polarized cells (e.g., enterocytes, hepatocytes, renal tubular cells, brain capillary endothelial cells), which plays a significant role in directional drug transport .

Permeability

The ability of a drug to pass through biological membranes. It is influenced by factors like lipid solubility (Pow). Drugs with high lipid solubility diffuse across cell membranes quickly until equilibrium is reached

Fick's Law of Diffusion

Describes that a drug will flow from an area of higher concentration to an area of lower concentration, with the rate of flow being higher with larger concentration gradients .

pgp localization

favours preferential transport of substrates out of tissues and into blood feces urine, etc

transporters can lead to

theraputic failure or improve efficacy/safety