Introduction to Pharmacokinetics

1. What is Pharmacokinetics?

Pharmacokinetics is the study of the movement of drugs within the body, encompassing the following processes:

• Absorption: The process by which a drug enters the body from its site of administration.
• Distribution: The process by which a drug is transported from the bloodstream to various tissues and organs in the body.
• Metabolism: The process by which a drug is chemically transformed in the body, often into inactive metabolites.
• Excretion: The process by which a drug and its metabolites are eliminated from the body.

2. Drug Transport Mechanisms Across Biological Membranes

There are four major mechanisms of drug transport across biological membranes:

• Passive Transport: Movement of a drug across a membrane from an area of high concentration to an area of low concentration, following the concentration gradient. This process relies on the drug’s solubility in water and lipids.
• Conditions:
• The drug is minimally ionized.
• The drug has a high concentration at the membrane surface.
• Diffusion of weak acids and bases depends on:
• The drug’s pKa (dissociation constant).
• The pH of the environment.
• Example: Aspirin (a weak acid) is well-absorbed in the stomach due to its low pH (1-3).
• Facilitated Diffusion: Transport of small (100-200 molecular weight) water-soluble drugs through membrane pores or channels, driven by hydrostatic pressure.
• Active Transport: Movement of a drug across a membrane against its concentration gradient, requiring the presence of specific membrane proteins called carriers.
• Characteristics:
• Saturation (limited number of carriers).
• Specificity (carriers bind only to specific drugs).
• Competition (drugs compete for carriers, those with higher affinity bind more).
• Inhibition (e.g., actinomycin D inhibits carrier proteins).
• Types:
• Facilitated Transport (Secondary Active Transport): Carrier-mediated, driven by concentration gradients, does not require energy.
• True Active Transport (Primary Active Transport): Moves a drug from low to high concentration (against the gradient), requiring energy.
• Examples:
• Facilitated Transport: Glucose, pyramidon transported along the concentration gradient of Na+.
• True Active Transport: Transport of Na+, K+, Ca++, I-, amino acids.
• Endocytosis: The process by which a cell membrane engulfs an exogenous substance, forming a vesicle that transports the substance across the membrane and releases it into the cell.
• Example: Insulin.

3. Pharmacokinetic Processes

3.1. Absorption

Factors Influencing Absorption:

• Drug Solubility: Water-soluble > lipid-soluble, gels, solids.
• pH at the site of absorption.
• Drug concentration at the site of absorption.
• Blood flow to the absorption site: Higher blood flow -> faster absorption.
• Surface area of absorption: Larger surface area (e.g., pulmonary epithelium) -> faster absorption. Small intestine > large intestine.
• Route of administration.

Some drugs are destroyed by:

• Digestive enzymes, intestinal cells, lung cells, liver cells.

Advantages and Disadvantages of the Gastrointestinal Tract:

• Advantages: Easy to use.
• Disadvantages:
• First-pass effect (metabolism in the liver).
• Formation of complexes with food.
• Stimulation of gastrointestinal mucosa, ulcers.

Gastrointestinal Routes:

• Sublingual: Not subject to enzymatic breakdown, avoids first-pass metabolism, often used in emergencies.
• Oral: Stomach pH (1-3) favorable for absorption of weak acids, minimally ionized (aspirin, barbiturates, phenylbutazone…). Small intestine (pH 6-8) is the primary site of absorption for many drugs due to its large surface area and extensive capillary network.
• Rectal: Used when vomiting, in a coma, or in children. Not subject to enzymatic breakdown, first-pass metabolism reduced by 50%.

3.2. Distribution

Drug Binding to Plasma Proteins: The portion of a drug bound to plasma proteins (albumin, a1-glycoprotein) is inactive.

Free Drug: The portion of a drug not bound to plasma proteins circulates in the bloodstream and can cross into tissues, where it exerts its effect, is stored in tissues, metabolized, or excreted.

Concentration of Free Drug and Drug-Protein Complex: There is always a dynamic equilibrium between these two forms.

Factors Influencing Distribution:

• Body: Nature of cell membranes, capillary membranes, pH, number of drug-binding sites.
• Drug: Molecular weight, water and lipid solubility, acid-base properties, degree of ionization, drug affinity for receptors…

3.3. Metabolism

Chemical Transformation: A drug is converted into metabolites, often less active than the parent drug.

Primarily Occurs in the Liver: Liver microsomal enzymes (cytochrome P450) play a major role in this process.

• Phase I: Oxidation, hydrolysis, reduction.
• Phase II: Conjugation (attachment to endogenous molecules to form water-soluble compounds).

Factors Influencing Metabolism:

• Age, genetics, exogenous factors, pathological conditions.

Metabolites can be:

• More active than the parent drug.
• Inactive.
• Toxic.

Some drugs are not metabolized: Barbiturates, ether, methotrexate, hexamethonium.

3.4. Excretion

Main Excretion Route: Kidney (passive filtration through the glomerulus, active secretion in the proximal convoluted tubule, passive diffusion in the proximal and distal convoluted tubules).

Other Excretion Routes: Lungs, bile (liver-gut), breast milk, saliva, sweat, tears, skin cells.

Clearance (CL): The ability of an organ to completely eliminate a drug from the plasma during one blood circulation through that organ.

• Significance: Dosage calculation, dosage adjustment in cases of liver or kidney failure.

Half-life (T1/2): The time required for the plasma concentration of a drug to decrease by half.

• Significance: Determines drug dosing intervals, estimates the time to reach steady-state concentration, and the time for complete drug elimination.

4. Pharmacokinetic Parameters

• Bioavailability (F): The percentage of an administered dose that reaches the systemic circulation in an active form.
• Significance: Reflects drug absorption, changes in chemical structure, changes in drug formulation.
• Clearance (CL): Represents the ability of an organ to eliminate a drug from the plasma during one circulation of blood through that organ.
• Volume of Distribution (Vd): Indicates the volume of body fluid in which a drug would need to distribute to achieve the same concentration as in the plasma.

5. Applications of Pharmacokinetics

• Selection of Drug Administration Route: Based on the drug’s absorption characteristics.
• Dosage Design: Based on pharmacokinetic parameters (T1/2, F, CL, Vd).
• Monitoring Drug Efficacy: Determination of plasma drug concentration.
• Dosage Adjustment in Cases of: Liver or kidney failure, diseases affecting drug absorption, metabolism, or excretion.
• Drug Interaction Studies: Determining the effects of one drug on the absorption, metabolism, or excretion of another drug.

In conclusion, Pharmacokinetics is an essential area of study for understanding how drugs act in the body, helping to design effective drug dosages and monitor drug efficacy.