Physiochemical Properties and Permeability Applied to Renal Drugs

lipophilicity, ionization, solubility

physiochemical properties

invention, discovery, design, and preparation of biologically active compounds + study of metabolism + structure-activity relationships (SAR). basically: it's the science of why a drug's structure makes it effective or toxic.

medicinal chemistry

formulation, stability, dosage form

pharmaceutical properties

target binding, potency

pharmacological properties

off-target effects, organ toxicity

toxicological properties

_________________ on a drug → determine hydrogen bonding, metabolism, ionization → which determines absorption, excretion, and safety.

functional groups

__________________ is why one enantiomer might be therapeutic while another is toxic (classic case: thalidomide).

3D drug structure

how much a drug "likes" fat/nonpolar environments.

lipophilicity

partitions into non-polar matrices (like membranes or hydrophobic protein pockets).

a lipophilic drug

important for: binding to hydrophobic receptor sites (pharmacology), crossing lipid cell membranes (oral absorption, distribution), potential toxic binding (like hERG channel → cardiac arrhythmias), and formulation into liposomes/surfactants.

lipophilicity

how much a drug "likes" water/polar environments.

hydrophilicity

partitions into polar matrices (like blood plasma, urine).

a hydrophilic drug

important for solubility, renal excretion, and IV formulation.

hydrophilicity

too lipophilic →

poor solubility & accumulation

too hydrophilic →

poor absorption across membranes

contribution of a specific functional group to lipophilicity.

π value

positive π →

lipophilic (phenyl, Cl, alkyl carbons)

negative π →

hydrophilic (SO₂, N, amides)

measure of overall lipophilicity.

LogP

drives absorption and tissue penetration.

lipophilicity

drives solubility and elimination.

hydrophilicity

protonated (unionized acid form).

HA

deprotonated (ionized conjugate base).

A-

ionized (A⁻) at high pH, unionized at low pH.

acids (HA)

ionized (BH⁺) at low pH, unionized at high pH.

bases (B)

more lipophilic → better membrane crossing.

unionized form

more hydrophilic → better solubility and renal elimination.

ionized form

lower pKa:

stronger acid (dissociates more easily).

carboxylic acid drugs (like NSAIDs, loop diuretics) are stronger acids and likely ___________________ at physiologic pH (~7.4).

ionized

sulfonamides are much weaker acids, more ____________________.

unionized

weak bases (like anilines) may remain unionized →

can cross membranes.

strong bases (guanidines, aliphatic amines) stay ionized at pH 7.4 →

soluble but poorly permeable.

______________ pH (1-2): stomach → acids stay unionized, bases become ionized.

low

____________________ pH (>8): sometimes used in formulations for salt formation (increase solubility).

high

furosemide: carboxylic acid with pKa = 3.9.

at pH 7.4, ___________________ → almost 100% ionized (carboxylate anion).

→ more water soluble, less membrane permeable → stays in renal lumen → perfect for diuretic action.

pH > pKa

torsemide:

pKa = 7.1.

at pH 7.4, close to pKa → about 50% ionized, 50% unionized.

→ balanced solubility and permeability. _________________ fraction helps oral absorption, ________________ fraction helps renal activity.

unionized, ionized

more ionized at high pH → trapped in alkaline urine (good for renal excretion).

acids

more ionized at low pH → trapped in acidic compartments like stomach or lysosomes.

bases

the velocity (rate) at which a compound crosses a biological membrane.

permeability

oral drug absorption.

GI epithelium

systemic distribution.

blood capillary epithelium

where the drug needs to act.

target tissues

highly selective, excludes many hydrophilic drugs.

blood brain barrier

major sites of metabolism and elimination.

liver and kidney cells

between cells (minor route).

paracellular

vesicular uptake (minor for small drugs, more for biologics).

endocytosis

across cells: the major route.

transcellular

main mechanism for small-molecule drugs.

passive diffusion

important for charged, polar drugs (renal secretion, BBB pumps).

active transport

only very small molecules (≤180 Da) can slip between cells. happens in the GI tract or kidney glomerulus.

most drugs are too large → so this pathway is limited.

paracellular

cell engulfs material into vesicles. not significant for most small-molecule drugs.

more relevant for large peptides, proteins, nanoparticles.

endocytosis

the most important pathway for small-molecule drugs.

driven by: Brownian motion (random molecular movement) and concentration gradient (high → low).

passive transcellular diffusion

properties that favor passive diffusion:

all of the above

low Log P (

poor

high Log P (>3-4) → too lipophilic → poor __________________ in water

solubility

hydrophilic, ionized drugs → stay in ____________ (good for diuretics, antibiotics targeting UTIs).

urine

__________________ → cross membranes easily, distribute widely, may penetrate BBB.

lipophilic, neutral drugs