Pharmacokinetics: ADME Overview

Pharmacokinetics (ADME)

• Pharmacokinetics is the study of how drugs are absorbed, distributed, metabolized, and excreted.

1. Absorption

• Absorption is how drugs enter the bloodstream
• Includes oral cavity, pharynx, esophagus, stomach, small intestine, and other sites.
• Different drug delivery methods have different rates of absorption.
• Factors affecting absorption include the drug's properties (lipid solubility, ionization), the route of administration, and physiological conditions.

2. Distribution

• Distribution is how drugs are transported throughout the body
• Drugs are transported in the blood via the circulatory system.
• Factors affecting distribution include blood flow, drug binding to proteins, and the presence of barriers to the drug's passage (e.g. Blood Brain Barrier).

3. Metabolism

• Metabolism of drugs involves their chemical alteration in the body.
• Primarily occurs in the liver.
• Liver enzymes change drug structure
• Lipid-soluble drugs get converted to water-soluble forms(hydrophilic)
• This process can make a drug safer or more effective.
• Factors affecting metabolism include the presence of other drugs (drug interactions), genetic factors, and liver function.

4. Excretion

• Excretion is the removal of the drug or its metabolites from the body.
• Primarily occurs in the kidneys.
• Can also occur in the liver, lungs, sweat glands, etc.
• Two main routes: glomerular filtration and tubular secretion
• Drugs are filtered out through the nephron of the kidney.

Routes of Administration

• Various methods include intravenous, intramuscular, subcutaneous, topical, and oral among others.
• Factors like rapid or sustained effect, first-pass metabolism, and targeted delivery play a role.
• Oral administration may involve first-pass metabolism (50%). First-pass metabolism is when a drug is absorbed from the intestines and then goes through the liver, before reaching systemic circulation.

1. Drug Absorption

• Gastrointestinal tract is the primary site for oral drug absorption.
• First-pass metabolism can decrease bioavailability and the amount of drug reaching systemic circulation.
• Bioavailability is the proportion of administered drug reaching the systemic circulation.

(i) Gastrointestinal Tract

• Drugs can be absorbed via sublingual and oral routes using different forms.
• Rectal administration of suppositories and foams is another way of administration.

Gastric Emptying and Intestinal Surface Area

• Gastric emptying rate is a key factor in drug absorption from the gastrointestinal tract.
• The large surface area of the small intestine is important for drug absorption.

(ii) First-Pass Drug Metabolism

• Drugs absorbed from the gut enter the hepatic portal system and are metabolized by liver enzymes.
• Some drugs, therefore, lose potency or are rendered ineffective following this first pass through the liver. This is an important consideration during drug development and use.

(iii) Bioavailability

• Bioavailability of a drug is the fraction of a dose reaching systemic circulation.
• Factors affecting bioavailability include drug absorption, first-pass metabolism, and other factors.
• Food can influence bioavailability by affecting absorption.

2. Drug Distribution

• Protein Binding: Drugs can bind to proteins in the blood or in tissues, influencing their distribution and activity.
• Blood Flow: Blood flow to tissues affects the rate at which drugs reach target locations.
• Body Compartments: Drug distribution varies across different body compartments.
• Blood-Brain Barrier: The blood brain barrier limits certain drugs’ access to the brain
• Placental Barrier: The placental barrier limits drug entry into the fetus.
• Cell Membrane: Drug movement through cell membranes is crucial for drug action

(i) Protein Binding

• Acidic drugs bind primarily to albumin proteins in the blood.
• Basic drugs bind mainly to a₁-acid glycoprotein.

(ii) Blood Flow

• Rate of perfusion and membrane permeability will determine the rate at which drugs are deposited in specific tissues.
• Higher perfusion rate will cause faster distribution of drug.

(iii) Body Compartments

• Drugs accumulate in certain body compartments more than others.
• Blood-brain barrier prevents drugs’ penetration into the central nervous system.
• Acidic drugs can be ‘trapped’ in acidic regions.

(iv) Body Compartments: Placental Barrier

• The placental barrier affects the entry of certain drugs from the mother to the fetus.
• The lipid solubility of a drug relates to its ability to cross membrane barriers.

(iii) Cell Membrane

• Factors like the drug's lipid solubility, and properties affect the crossing of cell membranes.
• Drugs cross membrane barriers by passive diffusion/active transport etc.

3. Drug Metabolism

• Lipid solubility: Fat-soluble drugs need to be converted to water-soluble forms to be excreted.
• Phase I drug metabolism: Oxidation, reduction, or hydrolysis reactions that chemically alter the drug molecule to make it more hydrophilic or to facilitate further metabolism, mostly in the liver.
• Phase II drug metabolism: Conjugation reactions such as glucuronidation, sulfation, etc., further modify the drug to increase its water solubility and make it easier for excretion.
• Liver enzymes: Drug interactions occur involving liver enzymes that metabolise drugs.
• Genetic polymorphism: Variations in genes encoding liver enzymes can affect drug metabolism.
• Prodrugs: These are inactive drugs that are converted to active forms by the body.

4. Drug Excretion

• Kidneys are the main organs for drug excretion.
• Processes include glomerular filtration, active tubular secretion, and passive reabsorption.
• Factors like drug solubility and renal function influence the removal of drugs.

(i) Glomerular Filtration

• Drugs are filtered out through glomeruli in the kidneys.
• Lipid solubility and molecular size affect the filtering process.
• Unbound filtered drugs are excreted in the urine and unbound drugs are best filtered.

(ii) Active Tubular Secretion

• Drug molecules are actively pumped into the tubule of a nephron.
• This process clears drugs and their metabolites from the bloodstream
• Drug specificity will depend on their structure and properties.

(iii) Passive Tubular Diffusion

• Passive flow of drugs across gradients across the tubes in a kidney, depending on their lipid solubility.

Response to Drugs

• Drug response can vary greatly among patients and will depend on their characteristics.
• Genetic, age, and lifestyle factors influence drug responses.
• "One dose for all" is therefore not suitable in all cases.