Drug Properties & Metabolism: Impact on Biological Action

Posted on Jul 15, 2025 in Biotechnology

Physicochemical Properties & Biological Action

Physicochemical properties refer to the physical and chemical characteristics of a drug molecule that influence its behavior in biological systems. These properties play a crucial role in determining the drug’s absorption, distribution, metabolism, and excretion (ADME).

Key Physicochemical Properties

These properties include:

  1. Ionization
  2. Solubility
  3. Partition Coefficient
  4. Hydrogen Bonding
  5. Protein Binding
  6. Chelation
  7. Bioisosterism
  8. Geometrical Isomerism
  9. Optical Isomerism

Ionization

Ionization is a key physicochemical property that refers to the ability of a molecule to gain or lose protons (H+), leading to the formation of charged species (ions). The extent of ionization is determined by the pKa of the drug and the pH of the surrounding environment.

Ionization & Biological Action

  1. Solubility: Ionized drugs are more soluble in water, aiding in dissolution in aqueous environments like the gastrointestinal tract.
  2. Membrane Permeability: Non-ionized forms of a drug are more lipophilic, allowing them to cross membranes easily, whereas ionized forms struggle to penetrate lipid bilayers.
  3. Absorption & Distribution: Drugs must balance ionization to be absorbed efficiently. Weak acids absorb better in acidic environments, while weak bases absorb better in basic environments.
  4. Excretion: Ionized drugs are more water-soluble and are excreted more easily via the kidneys. Non-ionized drugs may undergo reabsorption.

By understanding ionization, medicinal chemists can optimize drug properties for better therapeutic action and bioavailability.

Solubility

Solubility is the ability of a substance (solute) to dissolve in a solvent to form a homogeneous solution. In the context of medicinal chemistry, drug solubility refers to the extent to which a drug dissolves in biological fluids (e.g., gastric juice, blood, or intestinal fluid).

Drugs must be sufficiently soluble in aqueous fluids to be absorbed, distributed, and transported effectively in the body.

Partition Coefficient

The partition coefficient is the ratio of a compound’s concentration in a lipophilic solvent to its concentration in a hydrophilic solvent at equilibrium.

It is expressed as:

P = [Drug]LIPID / [Drug]WATER

The hydrophilic and lipophilic nature of the drug is indicated by log P.

Hydrogen Bonding

Hydrogen bonding is a type of weak chemical interaction that occurs when a hydrogen atom (H) is shared between a donor and an electronegative acceptor.

It is of two types:

  • Intermolecular Hydrogen Bonding
  • Intramolecular Hydrogen Bonding

Bioisosterism

Before discussing bioisosterism, let’s first discuss isosterism.

Isosterism

Isosterism is the phenomenon where molecules or ions have the same number of atoms and a similar arrangement of electrons, leading to comparable physical and chemical properties. For example, N2 (Nitrogen) and CO (Carbon Monoxide):

  • Both have the same total number of electrons (14).
  • Both molecules have a triple bond between two atoms.
  • They have similar bond length and ionization energies.

The concept of isosterism was first introduced by Irving Langmuir in 1919.

Geometrical Isomerism

Geometrical isomers are stereoisomers that have a different arrangement of groups or atoms around double bonds.

They are of two types:

  • Cis-Isomer
  • Trans-Isomer

Geometrical Isomerism & Biological Action

Geometrical isomers can have different biological activities. For example, Cisplatin is an effective anticancer drug, while Transplatin is inactive.

Optical Isomerism

Optical isomerism occurs when molecules have the same chemical formula but exist in two mirror-image forms.

It is of two types:

  • Dextrorotatory
  • Levorotatory
  • Dextrorotatory: Rotates plane-polarized light to the right.
  • Levorotatory: Rotates plane-polarized light to the left.

Optical Isomerism & Biological Action

Optical isomers can have drastically different effects in a biological system. For example, L-Dopa is used to treat Parkinson’s disease, while D-Dopa is biologically inactive.

Drug Metabolism

Drug metabolism is also known as biotransformation. It is a process by which the body transforms a drug into more readily excretable forms.

The primary site for metabolism is the liver. Other sites include the kidneys, intestines, lungs, and plasma.

Metabolism usually involves enzymatic reactions in the liver that alter (change) the chemical structure of the drug. These reactions make the drug more water-soluble, thus making it easier to be eliminated from the body via urine or bile.

The metabolism of a drug usually converts:

  • Lipid Soluble → Water Soluble
  • Unionized → Ionized

Metabolism is crucial for a drug’s duration and intensity of action, as well as for its overall safety profile.

Drug Metabolism Outcomes

Metabolism usually leads to the conversion of:

  • Active Drug → Active Metabolite
  • Active Drug → Inactive Metabolite
  • Inactive Drug → Active Metabolite

Cytochrome P450 Enzymes

Cytochrome P450 (CYP) enzymes are a group of proteins in the body that help break down drugs, toxins, and other substances.

In Cytochrome P450, ‘P’ stands for pigment that has maximum light absorption at a wavelength of 450 nm.

Several families of CYP enzymes are involved in the metabolism of drugs. These are named as CYP followed by a number (denotes family), then an alphabet (subfamily), and again a number (specific isoform of the enzyme).

CYP3A4 forms the maximum hepatic content (26%) of CYP enzymes and is involved in the metabolism of the maximum percentage of drugs (33%).

Examples of CYP Enzymes

  • CYP3A4
  • CYP2D6
  • CYP2C19
  • CYP2C9
  • CYP1A2

Types of Metabolism Reactions

There are mainly two types of biotransformation reactions:

  • Phase I Reactions
  • Phase II Reactions

Phase I Reactions

These reactions introduce functional groups into the drug and include:

  • Oxidation
  • Reduction
  • Hydrolysis
  • Cyclization
  • Decyclization

Oxidation

Oxidation is the process of addition of oxygen or removal of hydrogen from a drug molecule. Oxidation is primarily mediated by enzymes like CYP450s and results in the formation of more polar metabolites, which can be easily excreted from the body.

Examples: Phenytoin, Phenobarbitone, Propranolol

Reduction

Reduction is the process of addition of hydrogen or removal of oxygen from a drug molecule. It is less common than oxidation.

Examples: Chloramphenicol, Warfarin

Hydrolysis

Breakdown of a drug molecule by the addition of water is known as hydrolysis. This is common among esters and amides. It is mediated by enzymes such as esterases, amidases, and peptidases.

Cyclization

In this process, a straight-chain compound is converted into a ring structure.

Example: Cycloguanil from Proguanil

Decyclization

It involves the opening up of the ring structure of a cyclic drug molecule.

Example: Barbiturates