Drug Properties and Optimization - 2

Stomach environment

Strongly acidic, around pH 1–3. Drugs need adequate solubility and acid stability; relatively little absorption occurs here.

Intestinal absorption

Most oral drug absorption occurs in the small intestine, which has a large surface area and pH around 5.5–7.5.

Bile salts

Compounds that form micelles and help solubilize lipophilic drugs in the intestine.

Intestinal passive diffusion

Drug movement from the intestinal lumen through epithelial membranes toward blood without direct energy input.

First-pass metabolism

Drug metabolism after intestinal absorption and passage through the liver, reducing the amount reaching systemic circulation.

Phase I metabolism

Enzymatic oxidation, reduction or hydrolysis that may introduce or expose functional groups.

Phase II metabolism

Conjugation reactions that attach chemical groups, often increasing polarity and facilitating elimination.

Plasma protein binding

Reversible association of drugs with blood proteins, producing free and protein-bound circulating fractions.

Renal clearance

Removal of drugs and metabolites through urine; water-soluble compounds are generally eliminated more readily.

ADME

Absorption, distribution, metabolism and excretion; processes influencing how much drug reaches its target.

Lipinski's Rule of Five

Guideline identifying possible oral absorption problems using molecular weight, hydrogen bonding and lipophilicity.

Rule of Five thresholds

Warning criteria: more than 5 H-bond donors, 10 acceptors, 500 Da molecular weight or calculated LogP 5.

Rule of Five interpretation

Two or more threshold violations suggest increased risk of poor oral absorption, but do not guarantee failure.

Hydrogen-bond donor counting

Count suitable OH and NH donor groups, not individual hydrogens; an NH₂ group counts as one donor.

Hydrogen-bond acceptor counting

Count atoms with available lone pairs; amide nitrogen is not an acceptor, while ester oxygens are.

Hydrogen bonding and permeability

More hydrogen-bonding capacity can favour water solubility but make passage through lipid membranes harder.

Molecular weight and permeability

Larger molecules often diffuse less readily through membranes and may be harder to dissolve or formulate.

LogP

Logarithm of the octanol-to-water partition coefficient for a neutral compound; higher values indicate greater lipophilicity.

LogD

Logarithm of octanol-to-water distribution at a specified pH, accounting for ionized and neutral drug forms.

LogP versus LogD

LogP describes neutral-species lipophilicity; LogD incorporates pH-dependent ionization.

Lipophilicity balance

Drugs need adequate aqueous solubility and membrane permeability; excessively high or low lipophilicity can hinder absorption.

LogD at pH 7.4

Physiologically relevant distribution measurement; values around 1–3 are suggested for many oral small molecules, not required.

Shake-flask method

Mix a drug with octanol and water, reach equilibrium, then measure concentrations in both phases.

HPLC lipophilicity measurement

Estimates LogP using retention on a calibrated chromatography column; greater retention generally indicates greater lipophilicity.

Drug permeability

Ability to cross biological barriers, influenced by lipophilicity, ionization, molecular size and hydrogen bonding.

PAMPA assay

Artificial lipid-membrane assay measuring mainly passive permeability; rapid and useful for early screening.

Caco-2 assay

Cultured intestinal-like cell assay reflecting passive and transporter-mediated movement; more complex than PAMPA.

Permeability assay procedure

Place drug in a donor compartment and measure its appearance in the receiver compartment over time.

BCS Class I

High solubility and high permeability; generally favourable for oral absorption.

BCS Class II

Low solubility and high permeability; dissolution or solubility can limit oral absorption.

BCS Class III

High solubility and low permeability; membrane transport can limit oral absorption.

BCS Class IV

Low solubility and low permeability; both properties present oral delivery challenges.

Metabolic stability

Resistance to enzymatic transformation, commonly assessed by measuring how quickly a compound disappears.

Cytochrome P450

Heme-containing enzymes with an iron centre that use oxygen and NADPH-derived electrons in many drug oxidations.

Oxidation susceptibility

Electron-rich molecular sites are often more susceptible to oxidation; donating and withdrawing groups affect electron density.

Common conjugation reactions

Glucuronidation, sulfation, acetylation and glutathione conjugation are examples of Phase II metabolism.

Microsomal versus plasma stability

Microsomal assays assess liver enzyme metabolism; plasma assays assess drug integrity in plasma, often using half-life.

Structure–property relationships

Connections between molecular structure and properties such as solubility, pKa, permeability, lipophilicity and stability.

Lead optimization

Repeatedly modify a lead compound, measure activity and properties, compare analogues and select beneficial changes.

Molecular modification strategies

Adding, deleting or substituting groups; changing chains or rings; simplifying structures; or reducing flexibility.

Bioisosteres

Replacement atoms or groups intended to preserve biological interactions while improving properties; may be classical or non-classical.

Chain and ring modifications

Changing chain length alters spacing between binding groups; changing ring size affects geometry, flexibility and activity.

Structure simplification

Removal of nonessential molecular features while retaining important binding interactions, potentially easing synthesis.

Stereocentres

Sources of chirality; enantiomers can differ in activity, metabolism and toxicity, and may complicate manufacturing.

Racemic mixture

Equal amounts of two enantiomers; the individual enantiomers should be evaluated separately.

Pharmacophore

Three-dimensional arrangement of key interaction features required for recognition of a biological target.

Pharmacophore sharing

Structurally different molecules can produce similar biological effects when they retain important spatial interaction features.