2.1 Absorption

Absorption is a crucial process in medicinal chemistry that determines how drugs enter the body and reach their target sites. This topic explores various routes of absorption, mechanisms involved, and factors affecting drug uptake. Understanding absorption is key to developing effective medications and optimizing their delivery.

From oral to parenteral routes, each method of drug administration has unique characteristics. Factors like physicochemical properties, formulation, and physiological conditions influence absorption. Bioavailability, absorption kinetics, and strategies to enhance drug uptake are essential concepts in designing effective treatments.

Routes of absorption

• Overview: The route of absorption is a critical factor in determining the bioavailability and therapeutic efficacy of a drug in medicinal chemistry
• Overview: Different routes of absorption have distinct advantages and limitations, and the choice of route depends on various factors such as the drug's properties, desired onset of action, and patient compliance

Oral absorption

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• Most common and convenient route of drug administration
• Involves absorption of the drug from the gastrointestinal tract (stomach and intestines)
• Suitable for drugs that are stable in the gastrointestinal environment and can withstand first-pass metabolism
• Examples: Tablets, capsules, syrups, and suspensions

Parenteral absorption

• Involves administration of drugs directly into the body, bypassing the gastrointestinal tract
• Includes intravenous, intramuscular, and subcutaneous routes
• Provides rapid onset of action and high bioavailability
• Examples: Injections, infusions, and implants

Topical absorption

• Involves application of drugs directly to the skin or mucous membranes
• Suitable for drugs that have local effects or can penetrate the skin barrier
• Avoids first-pass metabolism and gastrointestinal side effects
• Examples: Creams, ointments, patches, and gels

Rectal absorption

• Involves administration of drugs through the rectum
• Useful for drugs that are unstable in the gastrointestinal tract or cause gastrointestinal side effects
• Provides rapid absorption and avoids first-pass metabolism
• Examples: Suppositories and enemas

Pulmonary absorption

• Involves inhalation of drugs into the lungs
• Provides rapid absorption and high bioavailability due to the large surface area of the lungs
• Suitable for drugs that have local effects in the lungs or require rapid systemic action
• Examples: Inhalers, nebulizers, and nasal sprays

Mechanisms of absorption

• Overview: The mechanism of absorption determines how a drug crosses biological membranes and enters the systemic circulation
• Overview: Understanding the mechanisms of absorption is crucial for designing drugs with optimal bioavailability and targeting specific sites of action

Passive diffusion

• Occurs when a drug moves across a membrane from a region of high concentration to a region of low concentration
• Depends on the drug's lipophilicity, molecular size, and concentration gradient
• Does not require energy or specific transporters
• Examples: Small, lipophilic drugs like aspirin and acetaminophen

Carrier-mediated transport

• Involves specific transport proteins that facilitate the movement of drugs across membranes
• Can be either active transport (requires energy) or facilitated diffusion (does not require energy)
• Exhibits saturation kinetics and can be inhibited by competing substrates
• Examples: Amino acids, vitamins, and nucleosides

Endocytosis

• Involves engulfment of drugs by the cell membrane, forming vesicles that internalize the drug
• Can be receptor-mediated (specific) or fluid-phase (nonspecific)
• Suitable for large, polar molecules that cannot cross membranes by passive diffusion
• Examples: Peptides, proteins, and nanoparticles

Paracellular transport

• Occurs when drugs move through the intercellular spaces between epithelial cells
• Depends on the size and charge of the drug molecule and the tightness of the junctions between cells
• Limited by the small surface area available for absorption
• Examples: Hydrophilic drugs with low molecular weight

Factors affecting absorption

• Overview: Various factors can influence the absorption of drugs, leading to variability in bioavailability and therapeutic response
• Overview: Understanding these factors is essential for optimizing drug formulations and dosing regimens in medicinal chemistry

Physicochemical properties of drugs

• Lipophilicity: Highly lipophilic drugs tend to have better absorption due to their ability to cross biological membranes
• Molecular size: Smaller molecules generally have better absorption than larger molecules
• Ionization: The degree of ionization affects the drug's solubility and permeability across membranes
• Examples: Partition coefficient, molecular weight, and pKa

Formulation factors

• Excipients: Inactive ingredients in a formulation can affect drug release, dissolution, and absorption
• Dosage form: Different dosage forms (tablets, capsules, liquids) have different absorption profiles
• Particle size: Smaller particle sizes generally enhance dissolution and absorption
• Examples: Disintegrants, binders, and surfactants

Physiological factors

• Gastrointestinal pH: The pH of the gastrointestinal tract can affect drug ionization and solubility
• Gastrointestinal motility: Faster motility reduces the time available for drug absorption
• Presence of food: Food can delay gastric emptying, alter gastrointestinal pH, and interact with drugs
• Examples: Gastric acid secretion, intestinal transit time, and dietary components

Disease states

• Gastrointestinal disorders: Conditions like inflammatory bowel disease and celiac disease can impair drug absorption
• Hepatic and renal impairment: Reduced liver or kidney function can affect drug metabolism and elimination
• Cardiovascular diseases: Altered blood flow can influence drug distribution and absorption
• Examples: Crohn's disease, cirrhosis, and congestive heart failure

Bioavailability

• Overview: Bioavailability is a key concept in medicinal chemistry that describes the fraction of an administered dose that reaches the systemic circulation
• Overview: Bioavailability is influenced by various factors and can be determined using different methods

Definition of bioavailability

• Refers to the extent and rate at which a drug enters the systemic circulation and becomes available at the site of action
• Expressed as a percentage of the administered dose
• Affected by factors such as absorption, distribution, metabolism, and elimination

Factors influencing bioavailability

• Route of administration: Different routes have different degrees of bioavailability
• First-pass metabolism: Drugs absorbed from the gastrointestinal tract may undergo metabolism in the liver before reaching the systemic circulation
• Drug solubility and permeability: Poorly soluble or poorly permeable drugs may have limited bioavailability
• Examples: Presystemic metabolism, efflux transporters, and drug-drug interactions

Absolute vs relative bioavailability

• Absolute bioavailability compares the bioavailability of a drug administered by a particular route to that of an intravenous dose
• Relative bioavailability compares the bioavailability of a drug formulation to that of a reference formulation
• Helps in determining the most suitable route of administration and optimizing drug formulations

Methods for determining bioavailability

• Pharmacokinetic studies: Measuring drug concentrations in blood or plasma over time
• Area under the curve (AUC): Calculating the total drug exposure by integrating the concentration-time curve
• Urinary excretion: Measuring the amount of unchanged drug excreted in urine
• Examples: LC-MS/MS, HPLC, and radioimmunoassay

Absorption kinetics

• Overview: Absorption kinetics describes the rate and extent of drug absorption over time
• Overview: Understanding absorption kinetics is essential for determining dosing regimens and predicting drug concentrations in the body

Zero-order vs first-order kinetics

• Zero-order kinetics: The rate of absorption is constant and independent of drug concentration
• First-order kinetics: The rate of absorption is proportional to the drug concentration
• Most drugs follow first-order kinetics, while some formulations may exhibit zero-order kinetics

Absorption rate constant

• Represents the rate at which a drug is absorbed from the site of administration into the systemic circulation
• Determined by the slope of the absorption phase in a concentration-time curve
• Affected by factors such as drug solubility, permeability, and surface area available for absorption

Absorption half-life

• The time required for half of the drug to be absorbed from the site of administration
• Calculated using the absorption rate constant
• Shorter absorption half-lives indicate faster absorption and onset of action

Time to peak concentration

• The time at which the maximum drug concentration is achieved in the systemic circulation
• Depends on the rate of absorption and elimination
• Shorter time to peak concentration may be desirable for drugs requiring rapid onset of action
• Examples: Immediate-release vs sustained-release formulations

Enhancing drug absorption

• Overview: Various strategies can be employed to enhance drug absorption and improve bioavailability
• Overview: These strategies aim to overcome the barriers to absorption and deliver drugs more effectively to the target site

Prodrugs

• Inactive compounds that are converted to active drugs by metabolic processes in the body
• Designed to improve solubility, permeability, or stability of the parent drug
• Can be used to target specific tissues or reduce side effects
• Examples: Enalapril (prodrug of enalaprilat) and valacyclovir (prodrug of acyclovir)

Permeation enhancers

• Substances that increase the permeability of biological membranes, facilitating drug absorption
• Act by disrupting the lipid bilayer, opening tight junctions, or inhibiting efflux transporters
• Should be safe, effective, and reversible in their action
• Examples: Chitosan, bile salts, and fatty acids

Nanoparticle-based drug delivery

• Involves encapsulating drugs in nanoscale carriers such as liposomes, polymeric nanoparticles, or dendrimers
• Enhances drug solubility, stability, and permeability across biological barriers
• Can target specific tissues or cells by surface modification with ligands
• Examples: Doxil (liposomal doxorubicin) and Abraxane (albumin-bound paclitaxel)

Targeted drug delivery strategies

• Aims to deliver drugs specifically to the site of action, minimizing systemic exposure and side effects
• Can be achieved by exploiting differences in pH, enzymes, or receptors between target and non-target tissues
• Includes antibody-drug conjugates, receptor-mediated endocytosis, and magnetic targeting
• Examples: Kadcyla (trastuzumab emtansine) and Onivyde (liposomal irinotecan)

Barriers to absorption

• Overview: Several physiological barriers can hinder the absorption of drugs and limit their bioavailability
• Overview: Understanding these barriers is crucial for designing drugs and delivery systems that can overcome them effectively

Gastrointestinal barriers

• Includes the acidic environment of the stomach, digestive enzymes, and mucus layer
• Can degrade or inactivate certain drugs, reducing their absorption
• Drugs may also bind to food components or chelate with ions, reducing their availability for absorption
• Examples: Peptide drugs and acid-labile compounds

Blood-brain barrier

• A highly selective semipermeable membrane that separates the circulating blood from the brain and extracellular fluid in the central nervous system
• Formed by tight junctions between endothelial cells and regulated by transporters and enzymes
• Restricts the passage of most drugs, except for small, lipophilic molecules
• Examples: Anticancer drugs and antibiotics

Skin barrier

• The outermost layer of the skin, the stratum corneum, acts as a barrier to drug absorption
• Consists of dead, keratinized cells embedded in a lipid matrix
• Limits the penetration of hydrophilic and high molecular weight drugs
• Examples: Topical corticosteroids and antifungal agents

Placental barrier

• A selective barrier that separates the maternal and fetal blood circulations
• Regulates the transfer of nutrients, oxygen, and waste products between the mother and fetus
• Can limit the passage of certain drugs, protecting the fetus from potential harm
• Examples: Teratogens and large molecular weight drugs

Drug-food interactions

• Overview: Interactions between drugs and food can have significant effects on drug absorption and bioavailability
• Overview: These interactions can lead to altered drug efficacy or increased risk of adverse effects

Types of drug-food interactions

• Pharmacokinetic interactions: Food can affect drug absorption, distribution, metabolism, or elimination
• Pharmacodynamic interactions: Food components can enhance or antagonize the pharmacological effects of drugs
• Physical interactions: Food can physically interact with drugs, altering their dissolution or stability
• Examples: Grapefruit juice-drug interactions and tetracycline-dairy interactions

Mechanisms of drug-food interactions

• Altered gastrointestinal pH: Food can change the pH of the gastrointestinal tract, affecting drug ionization and solubility
• Delayed gastric emptying: High-fat meals can slow down gastric emptying, delaying drug absorption
• Increased splanchnic blood flow: Food can increase blood flow to the gastrointestinal tract, enhancing drug absorption
• Examples: Ketoconazole and acidic beverages, and propranolol and protein-rich meals

Clinical significance of drug-food interactions

• Can lead to reduced or increased drug exposure, affecting therapeutic efficacy
• May cause adverse effects or toxicity due to altered drug concentrations
• Requires careful consideration when designing dosing regimens and patient counseling
• Examples: Warfarin and vitamin K-rich foods, and monoamine oxidase inhibitors and tyramine-containing foods

In vitro absorption studies

• Overview: In vitro absorption studies are conducted to predict drug absorption in the gastrointestinal tract and guide formulation development
• Overview: These studies use cell-based models or isolated tissues to assess drug permeability and transport

Caco-2 cell model

• A human colon carcinoma cell line that differentiates into enterocyte-like cells when cultured
• Forms tight junctions and expresses various transporters and enzymes similar to the small intestine
• Used to study passive diffusion, active transport, and efflux of drugs
• Correlates well with in vivo absorption for many drugs

Ussing chamber technique

• Uses excised intestinal tissue mounted between two chambers
• Allows measurement of drug transport across the tissue under controlled conditions
• Can assess the effects of formulation components, pH, and permeation enhancers on drug absorption
• Provides information on the directionality and mechanism of drug transport

Everted gut sac method

• Involves everting a segment of the small intestine and filling it with a drug solution
• The sac is incubated in an oxygenated buffer, and drug transport is measured
• Allows assessment of drug absorption, metabolism, and efflux in a more physiologically relevant model
• Can be used to study regional differences in drug absorption along the intestine

In vivo absorption studies

• Overview: In vivo absorption studies are conducted to assess drug absorption in living organisms
• Overview: These studies provide more clinically relevant information on drug bioavailability and pharmacokinetics

Animal models for absorption studies

• Commonly used animals include rats, mice, rabbits, and dogs
• Allow assessment of drug absorption, distribution, metabolism, and elimination in a living system
• Can be used to study the effects of formulation, dose, and route of administration on drug bioavailability
• Should be selected based on their anatomical and physiological similarities to humans

Human pharmacokinetic studies

• Involve administering the drug to healthy volunteers or patients and measuring drug concentrations in blood or plasma over time
• Provide the most clinically relevant information on drug absorption, bioavailability, and pharmacokinetics
• Can assess the effects of food, disease states, and drug-drug interactions on drug absorption
• Require careful design, ethical considerations, and regulatory approval

Imaging techniques for absorption studies

• Includes techniques such as gamma scintigraphy, positron emission tomography (PET), and magnetic resonance imaging (MRI)
• Allow non-invasive visualization and quantification of drug absorption and distribution in vivo
• Can provide real-time information on the fate of the drug in the body
• Examples: Gamma scintigraphy for assessing the gastrointestinal transit of oral dosage forms, and PET for studying the brain uptake of CNS drugs