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. , 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
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 that facilitate the movement of drugs across membranes
Can be either (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
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 , 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 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