Biopharmaceutics and Pharmacokinetics Factors Affecting Drug Kinetics

Main ideas / lessons

• Drug kinetics and biopharmaceutical performance are shaped by multiple factors that must be considered when designing dosage forms.
• These factors influence the drug’s ADME (Absorption, Distribution, Metabolism, Excretion) and therefore its:
  • bioavailability
  • absorption rate
  • distribution
  • extent of metabolism
  • elimination

• Both:

  • physiological factors (body conditions, route, GI behavior, metabolism capacity) and
  • physicochemical/formulation-related factors (solubility, particle size, crystal form, ionization, lipophilicity, stability) are central.

• Ultimately, understanding how a drug moves through tissues—including residence time and shunting/recycling—is important for effective and safe dosing.

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Key concepts and factor breakdown (detailed)

1) Dosage-form / physicochemical factors affecting absorption & kinetics

Particle size

• Smaller particles → higher surface area → faster dissolution/solubilization.
• Size effects are most pronounced for poorly water-soluble drugs.
• Techniques to reduce size and improve absorption:
  • Micronization
  • Solid dispersions (example: fine solid dispersions in polyethylene glycol, PEG)
  • Nanonization
• Examples:
  • Griseofulvin (neutral, low solubility ~15 µg/mL) has poor/erratic absorption; micronization improves it.
  • PEG-based solid dispersion can ~double absorption efficiency vs conventionally micronized formulations.
• Core idea: dispersing poor-solubility drugs in water-soluble polymers (e.g., PEG) can increase apparent solubility.

Crystal form / polymorphism

• Polymorphs differ in molecular packing/orientation → altered internal structure.
• Different crystal forms change density, solubility, melting point, influenced by intermolecular forces.
• General rule:
  • Weak attractive forces → less stable/high-energy lattice → higher solubility and faster dissolution.
  • Strongly stabilized lattice → less likely to dissolve.
• Design implication:
  • If energy differences between polymorphs are small, polymorphism may not noticeably affect absorption.
• Example:
  • Three polymorphs of chlorpropamide gave comparable serum levels due to similar internal structures.

Solubility (primary requirement for absorption)

• For absorption, the drug must become solubilized in solution at the absorption site.
• For oral drugs:
  • dissolution of the solid dosage form is a prerequisite for absorption and systemic circulation.
• Solubility depends on:
  • Polarity: polar compounds dissolve better in water; nonpolar dissolve better in organic phases.
  • Ionization state:
    • Ionized species generally have greater aqueous solubility than unionized species.
    • pH-dependent solubility: for weak acids/bases, solubility varies with local pH (stomach vs blood).
• Absorption relationship:
  • Lower aqueous solubility → slower absorption
  • Higher aqueous solubility → more absorption
• Topical (vaginal/rectal/dermal) considerations:
  • Drug must dissolve in the vehicle/carrier.
  • For a given vehicle, driving force is highest when:
    • drug concentration in vehicle ≈ drug solubility in vehicle
  • Below solubility → lower efficiency; above solubility → reservoir effect (depot behavior).

Ionization / pH effects on membrane transport

• Only unionized species penetrate lipoidal (lipid) membranes.
• GI absorption rate relates to the concentration of unionized drug at the site.
• pKa helps predict where the drug is most likely unionized → better passive diffusion.
• Reported examples/trends:
  • Drugs with pKa ~5–7 absorb readily compared with acidic drugs with high pKa.
  • Zwitterions (amphoteric compounds): minimal absorption difficulties.
  • Neutral compounds: no pH-dependent absorption.
• pH trend across pH 1–8:
  • Acids (pKa ~2.5–7.5): unionized fraction decreases as pH increases.
  • Bases (pKa ~5–11): unionized fraction increases as pH increases.
• Formulation strategies:
  • Choose formulation so controlled ionization occurs (avoid ionization conditions that prevent membrane passage).
  • Described as pH-independent absorption for:
    • weak acids with pKa > 7.5
    • bases with pKa < 5
  • Alternatives:
    • Enteric coating to avoid pH regions that cause ionization
    • Change absorption site (stomach vs intestine)

Lipophilicity / partition coefficient

• Partition coefficient (often via Log P) relates to distribution between lipid and aqueous phases.
• Key transport concept:
  • Unionized form → greater lipid solubility → better passive membrane transport
  • Ionized form → better aqueous solubility → less passive lipid diffusion
• Distribution implications:
  • Higher lipophilicity can improve brain access (BBB crossing) but may reduce solubility in blood.
  • Too low water solubility → poor membrane availability → poor absorption.
  • Too low lipophilicity → dissolves but can’t cross membrane → limited distribution.
  • Excessive lipophilicity → risk of accumulation in fatty tissue.
• Rule-of-thumb:
  • Log P > 1 → lipophilic
  • Log P < 1 → hydrophilic
• Design implication:
  • Structural modifications may be required to balance hydrophilicity/lipophilicity.

Stability (chemical integrity)

• The drug must remain stable:
  • until delivered, and
  • in vivo (not only during storage).
• Instability in formulation or before crossing the initial membrane can reduce bioavailability.
• Stability-related factors:
  • pH sensitivity
    • Acid-labile drugs degrade in the stomach
    • Enteric-coated tablets protect oral acid-labile drugs
  • Salt formation
    • Often improves aqueous solubility (treated as a chemical modification)
  • Oxidative and hydrolytic degradation
    • Example: Vitamin C is oxidation-sensitive
  • Storage conditions
    • Light, temperature, humidity can reduce effectiveness

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2) Metabolic factors (mostly liver; also enzyme-related)

• Metabolism occurs mainly via enzymes (especially in the liver).
• Factors affecting metabolism:
  • Genetic differences (fast vs slow metabolizers)
  • Enzyme inhibition/induction from other patient medications:
    • Induction → faster metabolism (reduced effect)
    • Inhibition → drug accumulation (toxicity risk)
  • Impaired liver function → slowed metabolism

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3) Gastrointestinal (GI) tract factors influencing absorption and bioavailability

GI pH variation

• Weak acids absorb better in the stomach.
• Weak bases absorb better in the intestine.

Food–drug interactions

• Some drugs are optimized with food or taken empty to maximize absorption.
• Example:
  • Griseofulvin with food can increase residence time and improve absorption/solubilization conditions.

Enzymatic degradation

• Some drugs are destroyed before absorption.
• Example: insulin by digestive enzymes.

GI transit time / gastric emptying

• Slow gastric emptying → delayed absorption (noted in diabetes).
• Can be used strategically:
  • delay gastric emptying to enhance absorption of poorly soluble drugs
  • if food interferes, dose on an empty stomach and promote faster emptying

Where biotransformation occurs

• Drug can be metabolized in:
  • gut lumen
  • gut wall
  • liver
• Enzymes in the upper intestine can influence stability.
• Enzyme locations mentioned:
  • endoplasmic reticulum
  • mitochondria
  • cytosol
• Examples mentioned:
  • Phenol and estrone sulfokinases → exit through GI tract
  • Steroid alcohol sulfokinase → more localized in jejunal mucosa

Types of reactions

• Pre-conjugation reactions: oxidation, hydroxylation, dealkylation, N- & S-oxidation, reduction, hydrolysis
• Conjugative/synthetic reactions mediated by enzymes

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4) Physiological factors and route/site of administration

Route affects effective surface area and absorption

• Greater effective surface area at the application site → better absorption.
• For topical use, larger surface area increases absorption potential.

Examples of route effects

• Intravenous (IV): ~100% bioavailability (no absorption step; rapid action)
• Oral: subject to first-pass metabolism → slower response
• Inhalation: rapid systemic absorption → faster onset
• Transdermal:
  • multiple intervening tissues → delayed onset
  • can support sustained release (example: nicotine patch)
  • pathways include hair follicles/sweat/sebaceous glands and aqueous channels
  • penetration depends on vehicle diffusion, pH, and diffusion through stratum corneum/supporting tissues
• Intramuscular (IM) and subcutaneous (SC):
  • good bioavailability
  • IM uses large muscle mass for injections

Residence time (time at site before elimination/redistribution)

• Influences bioavailability.
• Injection/dermal notes:
  • Depot-like formulations: drug retained longer; higher solubility in formulation than in tissue → reservoir behavior → prolonged effect.
  • IV bolus: short residence time → rapid clearance.

GI motility and feeding status

• Delayed gastric emptying or decreased intestinal motility affects bioavailability along with:
  • where the drug sits along GI tract
  • drug type and physicochemical nature
  • food state (fed vs unfed)

Rectal administration residence time

• Controlled by:
  • leakage
  • defecation
  • upward migration into the lower bowel
• Shorter residence time → lower bioavailability.
• Leakage/defecation reduces absorption; it may also alter first-pass exposure (described as potentially reducing but can increase exposure).

Determinants of residence time

• Lipophilicity: more lipophilic drugs → longer tissue retention
• Protein binding: high binding → longer circulation time
• Molecular size: larger molecules → slower clearance

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5) Shunting and recycling (diversion from blood/systemic appearance)

Shunting

• Drug enters other body fluids/tissues before/after systemic circulation, potentially reducing systemic appearance.

Examples of shunting

• Hepatic shunting: bypasses liver metabolism → increases systemic bioavailability
• Pulmonary shunting: avoids lung metabolism → trapped in pulmonary circulation
• Lymphatic shunting:
  • reappears later systemically
  • major pathway for absorption of fatty substances
  • described proportion: about one-tenth of filtered fluid enters terminal lymphatic capillaries
  • lymphatics are more permeable, especially important for high molecular weight substances

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Takeaways / concluding lessons

• Drug kinetics and bioavailability depend on coordinated effects of:
  • physiological conditions
  • physicochemical properties
  • dosage form/formulation design
  • metabolism capacity and GI environment
  • residence time and distribution dynamics
  • shunting pathways
• When dosing repeatedly, elimination and body retention across dosing intervals matter to avoid unintended accumulation.
• Dosage regimen design should integrate:
  • dosage form type
  • patient factors (e.g., liver impairment affecting metabolism)
  • safety and efficacy considerations

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