2: Pharmacokinetics: ADME processes

Section 1: General Pharmacology: 2: Pharmacokinetics: ADME Processes

Pharmacokinetics (PK) describes "what the body does to the drug" – the quantitative study of drug movement through the body over time. It encompasses the four fundamental processes known as ADME: Absorption, Distribution, Metabolism, and Excretion. Understanding ADME is crucial for determining drug dosing regimens, routes of administration, and potential interactions.

1. Absorption: This is the process by which a drug enters the bloodstream from its site of administration. The rate and extent of absorption depend on:

   • Route of Administration: Intravenous (IV) bypasses absorption (100% bioavailability). Oral (PO) is common but complex due to the gastrointestinal (GI) environment. Others include intramuscular (IM), subcutaneous (SC), transdermal, inhalation, and sublingual.
   • Drug Properties: Molecular size, lipid solubility (lipophilicity favors absorption), degree of ionization (non-ionized forms are better absorbed; governed by pH and pKa), and formulation (e.g., tablets, capsules, sustained-release).
   • Physiological Factors: GI motility, pH, surface area, blood flow to the site, and the presence of food or other drugs.
   • First-Pass Effect (Pre-systemic Metabolism): Orally administered drugs absorbed via the portal vein pass through the liver before reaching systemic circulation. Significant hepatic metabolism or biliary excretion during this first pass reduces the drug's bioavailability.

2. Distribution: This refers to the reversible transfer of a drug from the bloodstream into tissues and body fluids. Key determinants include:

   • Blood Flow: Organs with high perfusion (e.g., brain, liver, kidneys) receive drug faster than less perfused tissues (e.g., fat, bone).
   • Capillary Permeability: Varies by tissue (e.g., leaky capillaries in liver/spleen, tight blood-brain barrier).
   • Plasma Protein Binding: Drugs bind to proteins like albumin (acidic drugs) and alpha-1-acid glycoprotein (basic drugs). Only the unbound (free) fraction is pharmacologically active and available for distribution/metabolism/excretion. Binding is reversible and can be a site for drug interactions.
   • Tissue Binding: Accumulation in specific tissues (e.g., fat, bone) can act as reservoirs.
   • Volume of Distribution ($V_d$): A theoretical volume describing how widely a drug disperses throughout the body relative to its plasma concentration. A high $V_d$ suggests extensive tissue distribution outside plasma.

3. Metabolism (Biotransformation): The enzymatic conversion of drugs into metabolites, primarily occurring in the liver (hepatocytes), but also in the gut, lungs, kidneys, and plasma. Goals include:

   • Making lipophilic drugs more water-soluble for excretion.
   • Inactivation of the drug (most common) or activation of prodrugs.
   • Phase I Reactions: Modify the drug molecule via oxidation (mainly Cytochrome P450 enzymes - CYP1A2, 2C9, 2C19, 2D6, 3A4), reduction, or hydrolysis. Often introduce or expose a functional group (-OH, -NH₂, -SH, -COOH).
   • Phase II Reactions: Conjugate the drug or its Phase I metabolite with endogenous molecules (e.g., glucuronic acid, sulfate, glycine, glutathione, acetate) via conjugation reactions, greatly increasing water solubility. Glucuronidation is a major pathway.
   • Enzyme Induction/Inhibition: Drugs can induce (increase) or inhibit (decrease) the activity of metabolizing enzymes (especially CYPs), leading to significant drug-drug interactions.

4. Excretion: The irreversible removal of the drug and its metabolites from the body. The primary routes are:

   • Renal Excretion: The most important route for water-soluble metabolites and unchanged drugs. Involves:
     • Glomerular Filtration: Passive process for unbound, low molecular weight drugs.
     • Active Tubular Secretion: Carrier-mediated (e.g., OAT, OCT systems) in the proximal tubule, efficient and saturable.
     • Tubular Reabsorption: Passive diffusion back into blood, influenced by urine pH (ion trapping) and lipophilicity.
   • Biliary Excretion/Fecal: Active transport into bile for elimination via feces. Some drugs may undergo enterohepatic recirculation.
   • Other Routes: Lungs (gases/volatile anesthetics), sweat, saliva, breast milk.