Pharmacokinetics: ADME Student Notes

Pharmacokinetics: ADME Overview

• Definition: Study of Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs.

Passage of Drugs Across Membranes

• Plasma Membrane: Composed of phospholipids, cholesterol, and proteins.

• Passive Diffusion: Most important for drug passage.

  • Moves down a concentration gradient.

  • Lipid-soluble (less charged) drugs pass more readily.

  • Most drugs are weak electrolytes; ionization affected by pH.

  • Small molecules pass through ion channels.

• Specialized Transport Processes: For large/hydrophilic molecules.

  • Carrier-mediated transport:

    • Facilitated diffusion (down gradient with carrier).

    • Active transport (against gradient with carrier).

  • Filtration: Pressure and size are important.

  • Endocytosis and Exocytosis: Minor role for drugs.

Membrane Penetration by Weak Electrolytes

• Weak acids (HA) ionize to A^- + H^+; weak bases (B) to BH^+ in acidic environments.

• Degree of ionization depends on drug pK_a and environmental pH.

• Example: Aspirin (weak acid, pKa = 3.4) absorbed in acidic stomach (predominantly un-ionized \text{HA} form). Codeine (weak base, pKa = 7.9) poorly absorbed in stomach (predominantly ionized \text{BH}^+ form).

Absorption

• Routes of Administration: Oral (PO), Intramuscular (IM), Intravenous (IV), Subcutaneous (SQ), Intradermal (ID), Inhalation (IH), Intrathecal (IT), Topical.

• Oral Ingestion (Enteral): Most common.

  • Advantages/Disadvantages: Vary widely.

  • Influenced by pH, mucosal surface, gastric emptying time, GI contents, and dosage forms (enteric-coated, sustained-release).

• Bioavailability (F): Rate and extent (amount) of drug absorption.

  • Absolute Bioavailability: F = (AUC{oral} \times \text{dose}{IV}) / (AUC{IV} \times \text{dose}{oral})

  • Relative Bioavailability: F = (AUC{oral} \times \text{dose}{IM}) / (AUC{IM} \times \text{dose}{oral})

• Bioequivalence: Chemically/pharmaceutically equivalent products produce comparable bioavailability.

• Therapeutic Equivalence: Chemically/pharmaceutically equivalent products produce same efficacy/toxicity.

• Problems with Oral Route: Drug inactivation in GIT, first-pass effect, enterohepatic circulation.

• Other Enteral Routes: Sublingual, buccal, rectal.

• Nomenclature: Brand Name, Chemical Name, Drug Product, Generic Name.

• Key Terms:

  • Onset: Time to pharmacological effect.

  • Duration: Length of pharmacological effectiveness.

  • Half-life (t_{1/2}): Time for drug concentration to reduce by 50\%

  • Minimum Effective Concentration (MEC): Lowest plasma concentration for therapeutic effect.

• First-Pass Drug Biotransformation: Drug concentration greatly reduced before reaching systemic circulation due to liver metabolism after oral ingestion.

  • Overcome by alternative routes (sublingual, IV).

• Enterohepatic Cycling/Circulation: Circulation of drugs from liver to bile, then small intestine for reabsorption (often after de-conjugation by gut bacteria), returning to liver via portal circulation.

  • Results in multiple peaks and longer apparent t_{1/2}.

Distribution

• Capillary Penetration & Entry into Cells: Limited by membrane barriers.

• Specialized Fluid Compartments:

  • Blood-Brain Barrier (BBB): Limits entry of charged/hydrophilic drugs into CNS.

  • Placenta transfer.

  • Salivary secretion.

• Volume of Distribution (V_d): A theoretical volume indicating how drugs disperse among body compartments.

  • V_d = Q/C (Q = quantity of drug administered; C = plasma concentration).

  • Higher V_d indicates more drug distributed in tissues, less in plasma.

  • Increased by high lipid solubility, low ionization, low plasma protein binding.

  • Affected by liver/renal failure (increases) and dehydration (decreases).

• Drug Binding and Storage:

  • Plasma Proteins: Drugs bind to albumin, globulins (\alpha_1-acid glycoprotein); finite binding sites (Law of Mass Action).

  • Tissue binding: Higher binding to plasma protein generally leads to longer duration and less frequent administration.

• Redistribution: Rapid movement of highly lipid-soluble drugs from highly perfused organs (e.g., brain) to less perfused lipid-rich tissues, affecting duration of action (e.g., thiopental).

Biotransformation (Metabolism)

• General: Major pathway for termination/excretion; converts drugs to polar compounds for easier elimination.

  • Products can be inactive, active, or toxic.

  • Prodrugs are inactive parent compounds converted to active products (e.g., levodopa to dopamine).

• Consequences: Active to inactive, prodrug to active, active to active metabolite.

• Sites: Liver (major), kidney, skin, lung, plasma, small intestine.

  • Cellular sites: Smooth endoplasmic reticulum (microsomes), lysosomes, mitochondria, cytosol.

• Enzymes: Microsomal (most common) or non-microsomal.

  • Microcosomal enzyme inducers/inhibitors affect co-administered drug concentrations.

• Phase I Reactions (Non-synthetic): Increase polarity by introducing reactive/polar groups.

  • Processes: Oxidation (most important, by microsomal enzyme oxidase, e.g., Cytochrome P450 system), Reduction, Hydrolysis, Dehalogenation, Dealkylation.

  • CYP450 system crucial; incorporates oxygen into lipophilic hydrocarbons.

  • Can convert prodrugs to active drugs or nontoxic molecules to toxic ones.

• Phase II Reactions (Conjugation): Produce polar metabolites by conjugating Phase I products with endogenous charged species (e.g., glucuronic acid, glutathione, sulfate, glycine).

  • Processes: Glucuronidation (most important), Sulfation, Acetylation, Alkylation.

  • Products have increased molecular weight, are usually less active, more polar, and readily excreted.

• Factors Affecting Drug Metabolism:

  • Liver enzymes (especially P450) and their activity (induction/inhibition).

  • Hepatic blood flow, plasma protein binding, diseases (liver, kidney, heart).

  • Dose, frequency, route, tissue distribution.

  • Age (very young/old).

  • Genetic factors (polymorphism, e.g., N-acetyltransferases leading to slow/rapid acetylators).

Excretion

• Routes: Urine, bile, sweat, saliva, pulmonary exhalation, tears, milk.

• Kidney: Major organ for excretion.

• Renal Excretion Processes:

  • Glomerular Filtration: Only free (unbound) drugs filtered.

  • Tubular Reabsorption: Water and electrolytes reabsorbed; polar metabolites cannot diffuse back.

  • Active Tubular Secretion: Energy-dependent carrier-mediated transport of metabolites from plasma to tubule (e.g., probenecid blocks penicillin secretion).

  • Urine pH: Affects ionization state of weak acids/bases, influencing reabsorption/excretion (acidification increases excretion of weak bases, decreases weak acids).

• Clearance (CL): Volume of plasma cleared of drug per unit time.

  • CL = (U \times V) / P (U = urine concentration, V = urine volume, P = plasma concentration).

  • Related to Vd and elimination rate constant (Ke): CL = Ke \times Vd

• Biliary Excretion (Fecal Elimination): For drugs with MW > 500

  • Active transport into bile.

  • Can undergo enterohepatic recycling, prolonging effects.

• Kinetics of Elimination:

  • Zero-order kinetics: Constant quantity eliminated per unit time, independent of concentration (dc/dt = k_0).

    • Occurs when elimination system is saturated (e.g., ethanol).

    • Risk of drug accumulation.

  • First-order kinetics: Constant fractional rate (proportion) eliminated per unit time (dc/dt = kc).

    • Rate is proportional to drug concentration; applies to most drugs.

  • Half-life (t_{1/2}): Time for drug concentration to fall to 50\%

    • t_{1/2} = 0.693 / K (K = elimination rate constant).

  • Capacity-limited reactions: Initially zero-order (saturation) then first-order as concentration falls (e.g., alcohol, aspirin).