3.2 Drug absorption and factors affecting absorption

Drug absorption is crucial for pharmacological effects. It involves the movement of drugs from administration sites to the bloodstream through biological membranes. Various mechanisms, including passive diffusion, facilitated diffusion, active transport, and endocytosis, facilitate this process.

Many factors influence drug absorption. These include physicochemical properties like lipophilicity and molecular size, physiological factors such as blood flow and pH, and the presence of transporters. Understanding these factors is essential for optimizing drug delivery and predicting drug behavior in the body.

Drug Absorption Mechanisms

Passive and Facilitated Diffusion

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• Drug absorption involves movement of drug molecules from administration site to bloodstream through biological membranes
• Passive diffusion drives drug absorption without energy expenditure
  • Drugs move from high to low concentration areas
  • Occurs for many small, lipophilic molecules
• Facilitated diffusion uses carrier proteins to assist transport
  • No energy input required
  • Typically used for larger or charged molecules
  • Examples: glucose transporters, ion channels
• Lipid bilayer structure of cell membranes impacts absorption
  • Lipophilic drugs (ibuprofen) cross more easily than hydrophilic ones (metformin)

Active Transport and Endocytosis

• Active transport moves drugs against concentration gradient
  • Requires energy and specific carrier proteins
  • Used for essential nutrients and some drugs
  • Examples: sodium-potassium pump, amino acid transporters
• Endocytosis involves cells engulfing substances
  • Used for absorption of large molecules or particle-based formulations
  • Types include phagocytosis and pinocytosis
  • Example: absorption of vitamin B12 in ileum
• Exocytosis expels substances from cells
  • Can be involved in secretion of drugs or metabolites
  • Example: neurotransmitter release at synapses

Factors Influencing Drug Absorption

Physicochemical Properties and Surface Area

• Lipophilicity affects membrane crossing ability
  • Highly lipophilic drugs (benzodiazepines) absorb more readily
  • Hydrophilic drugs (metformin) have limited passive diffusion
• Molecular size impacts absorption rate
  • Smaller molecules generally absorb faster
  • Large molecules may require specialized transport mechanisms
• Ionization state determined by drug pKa and environmental pH
  • Unionized forms typically absorb more readily
  • Example: weak acids absorb better in stomach, weak bases in intestine
• Surface area available for absorption varies by administration route
  • Small intestine provides largest surface area for oral drugs
  • Enhanced by presence of villi and microvilli
  • Transdermal absorption limited by skin surface area

Physiological Factors and Disease States

• Blood flow to absorption site impacts drug uptake rate
  • Highly perfused areas (lungs, brain) allow faster absorption
  • Exercise can increase blood flow and enhance absorption
• pH at absorption site alters drug ionization
  • Gastric pH (1-3) different from intestinal pH (6-8)
  • Can affect proportion of drug available for absorption
• Presence of food in gastrointestinal tract influences absorption
  • Can alter gastric emptying time (delayed with high-fat meals)
  • May change pH or directly interact with drug
  • Example: tetracyclines chelate with calcium in dairy products
• First-pass metabolism in liver reduces oral drug bioavailability
  • Significant for drugs like morphine and propranolol
  • Can result in much lower systemic exposure than administered dose
• Disease states affecting organ function alter absorption patterns
  • Gastrointestinal disorders (Crohn's disease) may reduce absorption
  • Liver disease can impair first-pass metabolism
  • Altered pH in conditions like achlorhydria impacts ionization

Transporters in Drug Absorption

Influx and Efflux Transporters

• Transporters facilitate movement of specific molecules across barriers
  • Specialized proteins embedded in cell membranes
  • Play crucial role in absorption of many drugs and nutrients
• Influx transporters actively move drugs into cells
  • Enhance absorption of certain compounds
  • Examples: organic anion transporting polypeptides (OATPs), peptide transporters
  • OATP1B1 involved in statin uptake in liver
• Efflux transporters pump drugs out of cells
  • Can limit absorption and contribute to drug resistance
  • P-glycoprotein (P-gp) is a well-known efflux transporter
  • P-gp limits absorption of drugs like digoxin and paclitaxel
• Transporter expression and activity vary among individuals
  • Genetic polymorphisms can affect drug absorption and efficacy
  • Example: variations in SLCO1B1 gene affecting statin pharmacokinetics

Transporter-Mediated Interactions and Pharmacokinetics

• Some drugs induce or inhibit transporter activity
  • Can lead to drug-drug interactions affecting absorption
  • Example: rifampicin induces P-gp, reducing digoxin absorption
• Transporter-mediated absorption is saturable
  • Can result in non-linear pharmacokinetics at high concentrations
  • Important consideration for drugs with narrow therapeutic index
• Understanding transporter mechanisms crucial for drug development
  • Informs strategies to enhance bioavailability
  • Allows targeting of specific tissues
  • Example: developing P-gp inhibitors to enhance brain penetration of certain drugs

Drug Formulation & Absorption

Pharmaceutical Forms and Release Mechanisms

• Pharmaceutical form significantly influences dissolution and absorption
  • Tablets, capsules, solutions have different absorption profiles
  • Solutions generally absorb faster than solid dosage forms
• Immediate-release formulations designed for rapid absorption
  • Quick onset of action for drugs like analgesics
  • Example: regular release acetaminophen tablets
• Modified-release formulations control rate and site of drug release
  • Include extended-release, delayed-release, and targeted-release
  • Examples: enteric-coated aspirin, extended-release metformin
• Particle size in solid dosage forms affects dissolution rate
  • Smaller particles generally allow faster dissolution
  • Micronization used to enhance absorption of poorly soluble drugs (griseofulvin)

Novel Delivery Systems and Bioequivalence

• Excipients impact absorption by altering drug properties
  • Can change solubility, stability, or membrane interaction
  • Example: cyclodextrins enhancing solubility of lipophilic drugs
• Novel drug delivery systems enhance absorption
  • Nanoparticles and liposomes protect drug from degradation
  • Can target specific absorption sites
  • Examples: liposomal amphotericin B, nanoparticle-based cancer drugs
• Route of administration directly impacts absorption process
  • Oral, transdermal, parenteral routes have distinct absorption profiles
  • Influences bioavailability of the drug
  • Example: transdermal fentanyl patch for sustained absorption
• Bioequivalence studies compare absorption profiles of formulations
  • Crucial for generic drug development and approval
  • Ensures therapeutic equivalence between brand-name and generic drugs
  • Typically involves comparing area under the curve (AUC) and maximum concentration (Cmax)