2.2 Distribution

Drug distribution determines how a drug moves from the bloodstream into tissues and organs after it's been administered. This process directly affects whether a drug reaches its target site at the right concentration, which in turn shapes both its therapeutic effects and side effects.

Factors like plasma protein binding, tissue affinity, and physiological barriers all govern how drugs spread through the body. Understanding these factors is essential for optimizing dosing regimens and predicting patient outcomes.

Routes of drug administration

The route of administration is the path by which a drug enters the body. It has a major impact on how quickly the drug works, how much reaches the bloodstream, and how well patients tolerate it. Route selection depends on the drug's physical and chemical properties, the clinical situation, and patient-specific factors.

Oral administration

The most common and convenient route. Drugs are swallowed and absorbed through the gastrointestinal (GI) tract, primarily in the stomach and small intestine.

• Advantages: Easy to administer, good patient compliance, cost-effective
• Disadvantages: Subject to first-pass metabolism (which can drastically reduce bioavailability), variable absorption depending on GI conditions, and potential GI side effects like nausea and vomiting

Parenteral administration

Parenteral means "bypassing the GI tract." Drugs are delivered directly into the body through injection.

• Routes include: intravenous (IV), intramuscular (IM), subcutaneous (SC), and intradermal
• Advantages: Rapid onset (especially IV), precise dosing, complete avoidance of first-pass metabolism
• Disadvantages: Invasive, carries infection risk, and typically requires trained personnel

Topical administration

Drugs are applied directly to the skin or mucous membranes (eyes, nose, ears) for either local or systemic effects.

• Advantages: Targeted delivery, fewer systemic side effects, easy to apply
• Disadvantages: Limited and variable absorption through the skin, potential for local irritation, difficulty controlling exact dose delivered

Rectal administration

Drugs are delivered through the rectum and absorbed via the rectal mucosa. This route is particularly useful when oral administration isn't feasible, such as in unconscious patients or those experiencing severe vomiting.

• Advantages: Partially avoids first-pass metabolism (the lower rectum drains into the systemic circulation, bypassing the portal vein), relatively rapid absorption
• Disadvantages: Limited patient acceptability, variable absorption, potential for rectal irritation

Inhalation

Drugs are delivered directly into the lungs, most commonly for respiratory conditions like asthma and COPD.

• Advantages: Very rapid onset due to the lungs' large surface area and rich blood supply, targeted delivery to airways, reduced systemic side effects
• Disadvantages: Dose control can be difficult (depends on inhalation technique), potential airway irritation, requires specialized devices like metered-dose inhalers or nebulizers

Factors affecting route selection

• Physicochemical properties of the drug (solubility, stability, molecular size)
• Desired onset and duration of action
• Target site of action (local vs. systemic)
• Patient factors (age, comorbidities, preference, ability to comply)
• Available formulations of the drug

Absorption of drugs

Absorption is the process by which a drug moves from its site of administration into the bloodstream. Both the rate and extent of absorption determine how quickly and how much drug becomes available to exert its effects.

Mechanisms of absorption

• Passive diffusion: Drug molecules move across membranes down their concentration gradient (high to low). No energy or carrier proteins required. This is the most common mechanism for drug absorption.
• Active transport: Carrier proteins use energy (ATP) to move drugs against their concentration gradient. This process is saturable and can be specifically inhibited.
• Facilitated diffusion: Carrier-mediated transport that moves drugs down their concentration gradient without energy input. Like active transport, it's saturable.
• Endocytosis: The cell membrane engulfs drug molecules, forming vesicles that carry the drug into the cell. This is relevant for large molecules like proteins.

Factors affecting absorption

• Drug properties: Lipophilicity, aqueous solubility, degree of ionization, molecular size
• Dosage form: Tablets, capsules, solutions, and suspensions all release drug at different rates
• Absorption site: GI tract, skin, and mucous membranes each have different permeability characteristics
• GI environment: pH (affects ionization), motility, presence of food, digestive enzymes, and membrane transporters
• Patient factors: Age, sex, genetic polymorphisms in metabolizing enzymes or transporters, disease states

Bioavailability

Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation in unchanged form. An IV dose has 100% bioavailability by definition, since the entire dose enters the bloodstream directly.

Oral bioavailability is typically lower because of two main losses: incomplete absorption from the GI tract and first-pass metabolism. Bioavailability is influenced by route of administration, dosage form, and individual patient factors.

First-pass metabolism

When an orally administered drug is absorbed from the GI tract, it travels via the portal vein to the liver before reaching the systemic circulation. During this "first pass," hepatic and intestinal enzymes can metabolize a significant portion of the drug, reducing the amount that actually enters the bloodstream.

Some drugs undergo extensive first-pass metabolism. Propranolol, for example, has oral bioavailability of only about 25% because of this effect. Lidocaine is so extensively metabolized on first pass that it's essentially ineffective when given orally.

Strategies to avoid first-pass metabolism include using parenteral, sublingual, or rectal routes, or designing prodrugs that are activated after reaching the systemic circulation.

Absorption rate vs. extent

These are two distinct concepts that are often confused:

• Rate of absorption refers to how quickly the drug enters the bloodstream. It determines the onset of action and peak plasma concentration. Factors include drug dissolution rate, GI motility, and blood flow at the absorption site.
• Extent of absorption refers to the total amount of drug that ultimately reaches the bloodstream. It determines the overall exposure (AUC). Factors include drug solubility, membrane permeability, and first-pass metabolism.

Two formulations of the same drug can have the same extent of absorption but very different rates, which is why bioequivalence studies measure both.

Distribution of drugs

Distribution is the reversible transfer of drug from the bloodstream into the interstitial fluid (between cells) and into tissues. Once a drug is absorbed, distribution determines where in the body it goes, how much reaches the target, and how much ends up in off-target sites.

Factors affecting distribution

• Lipophilicity: More lipophilic drugs cross membranes more easily and distribute more widely
• Ionization: Unionized forms cross membranes; ionized forms are trapped (ion trapping)
• Molecular size: Smaller molecules distribute more readily
• Protein binding: Only unbound drug distributes into tissues
• Tissue perfusion: Highly perfused organs (brain, heart, kidneys, liver) receive drug first; poorly perfused tissues (fat, bone) receive drug later
• Tissue affinity: Some drugs bind preferentially to certain tissues
• Physiological barriers: The blood-brain barrier, blood-testis barrier, and blood-placenta barrier restrict entry into specific compartments

Plasma protein binding

Most drugs bind reversibly to plasma proteins once in the bloodstream. The major binding proteins are albumin (binds acidic drugs primarily), $\alpha_1$-acid glycoprotein (binds basic drugs), and lipoproteins.

The bound fraction is pharmacologically inactive. It can't cross membranes, interact with receptors, or be eliminated. Only the free (unbound) fraction is active and available for distribution and clearance.

This matters clinically because if two drugs compete for the same binding site on albumin, one can displace the other, temporarily increasing the free concentration of the displaced drug. In highly protein-bound drugs (>90% bound), even a small displacement can cause a large relative increase in free drug and potentially lead to toxicity.

Tissue binding

Drugs can also bind within tissues, either to their pharmacological targets (specific binding) or to proteins, lipids, and other macromolecules (nonspecific binding).

Tissue binding can act as a drug reservoir. For example:

• Digoxin binds extensively to cardiac and skeletal muscle, giving it a very large volume of distribution
• Thiopental initially acts on the brain (highly perfused) but then redistributes into adipose tissue, where it accumulates due to its high lipophilicity

Blood-brain barrier

The blood-brain barrier (BBB) is formed by tight junctions between endothelial cells lining brain capillaries. Unlike capillaries elsewhere in the body, brain capillaries have no fenestrations (gaps), so drugs can't slip through paracellularly.

To cross the BBB, a drug generally needs to be:

• Lipophilic
• Small (typically < 400-500 Da)
• Unionized at physiological pH

Efflux transporters, particularly P-glycoprotein (P-gp), actively pump many drugs back out of the brain, further limiting CNS penetration. This is why designing drugs that effectively treat CNS conditions is so challenging.

The BBB can become more permeable in pathological states like meningitis, brain tumors, or inflammation, which can alter drug distribution into the CNS.

Volume of distribution

The volume of distribution ($V_d$) is a theoretical parameter that relates the total amount of drug in the body to its plasma concentration:

$V_d = \frac{\text{Amount of drug in body}}{\text{Plasma concentration}}$

$V_d$ does not correspond to an actual physiological volume. It tells you how extensively a drug distributes out of the plasma and into tissues.

• Low $V_d$ (< 0.3 L/kg): Drug stays mostly in the bloodstream. Examples: heparin (~0.06 L/kg), warfarin (~0.15 L/kg). These drugs are often highly protein-bound or too hydrophilic to cross membranes easily.
• High $V_d$ (> 1 L/kg): Drug distributes extensively into tissues. Examples: digoxin (~7 L/kg), chloroquine (~200 L/kg). These drugs have high tissue affinity.

A $V_d$ greater than total body water (~0.6 L/kg or ~42 L for a 70 kg person) means the drug concentrates in tissues at higher levels than in plasma.

Drug transport mechanisms

Drugs cross biological membranes through several distinct mechanisms. The mechanism involved affects the rate, extent, and selectivity of drug movement.

Passive diffusion

The most common transport mechanism for drugs. Molecules move down their concentration gradient without energy input or carrier proteins. The rate depends on the drug's lipophilicity, molecular size, and the magnitude of the concentration gradient.

Passive diffusion follows Fick's law: the rate of diffusion is proportional to the concentration difference across the membrane, the membrane surface area, and the drug's partition coefficient, and inversely proportional to membrane thickness.

Small, lipophilic, uncharged molecules diffuse most readily (e.g., oxygen, ethanol, steroid hormones).

Active transport

Energy-dependent transport that moves drugs against their concentration gradient using carrier proteins. The energy source is typically ATP hydrolysis or coupling to an electrochemical gradient (e.g., sodium or proton gradients).

Key characteristics:

• Saturable: There's a maximum transport rate ($V_{max}$) once all carrier proteins are occupied
• Specific: Transporters recognize particular substrates
• Inhibitable: Can be blocked by competitive inhibitors

Clinically important examples include P-glycoprotein (effluxes many drugs out of cells), OATP transporters (hepatic uptake of statins), and renal transporters (secretion of penicillins).

Facilitated diffusion

Like active transport, this uses carrier proteins, but it moves drugs down their concentration gradient and requires no energy. It's saturable and subject to competitive inhibition, just like active transport.

Examples include nucleoside transporters and the norepinephrine transporter (NET).

Ion channels

Transmembrane proteins that form selective pores for ions ($Na^+$, $K^+$, $Ca^{2+}$, $Cl^-$). They can be:

• Voltage-gated: Open or close in response to changes in membrane potential
• Ligand-gated: Open or close when a specific molecule binds

Many drugs act as ion channel modulators. Local anesthetics block voltage-gated sodium channels, and benzodiazepines enhance chloride flow through GABA-gated channels.

Endocytosis and exocytosis

• Endocytosis: The cell membrane invaginates to engulf extracellular material, forming intracellular vesicles. Can be receptor-mediated (clathrin-coated pits) or nonspecific (pinocytosis). This is how large molecules like antibody-drug conjugates and some nanoparticle formulations enter cells.
• Exocytosis: Intracellular vesicles fuse with the cell membrane to release their contents outside the cell. This is the mechanism for neurotransmitter and hormone release.

Drug reservoirs

Certain tissues accumulate drugs and release them slowly over time, acting as reservoirs. These reservoirs can prolong a drug's duration of action but also create the potential for delayed toxicity.

Adipose tissue

Highly lipophilic drugs partition into fat stores due to their affinity for lipids. Because adipose tissue has relatively low blood flow, drugs accumulate slowly but are also released slowly.

• Thiopental is a classic example: after IV administration, it rapidly enters the brain (causing anesthesia) but then redistributes into fat, where it can persist for hours
• Chloroquine and DDT also accumulate in adipose tissue
• In obese patients, lipophilic drugs may have significantly altered distribution and prolonged elimination

Bone

Some drugs bind to the hydroxyapatite mineral matrix of bone or to calcium within bone.

• Tetracyclines chelate calcium and deposit in developing bones and teeth, which is why they're contraindicated in children under 8 and pregnant women (causes permanent tooth discoloration)
• Bisphosphonates (used to treat osteoporosis) bind tightly to bone and can persist for years
• Lead accumulates in bone and is released slowly, contributing to chronic toxicity

Transcellular vs. interstitial fluid

Drug distribution between fluid compartments depends on physicochemical properties:

• Interstitial fluid (between cells): Hydrophilic drugs that can't easily cross cell membranes tend to remain here
• Intracellular fluid (inside cells): Lipophilic drugs cross membranes readily and access this larger compartment

The relative distribution between these compartments affects both pharmacological activity (is the target intracellular or extracellular?) and elimination kinetics.

Redistribution of drugs

Redistribution occurs when a drug moves from one tissue compartment to another over time, driven by changing concentration gradients. This is distinct from initial distribution and can have major clinical consequences.

Factors affecting redistribution

• Tissue perfusion: Drugs initially concentrate in highly perfused organs (brain, heart, kidneys). As plasma levels fall, drug moves down its concentration gradient into less perfused tissues (muscle, fat).
• Tissue binding affinity: Drugs redistribute from sites of lower affinity to sites of higher affinity as equilibrium shifts.
• Lipophilicity: Lipophilic drugs redistribute between compartments more readily than hydrophilic drugs.
• Changes in plasma protein binding: Displacement from plasma proteins increases free drug concentration, which can drive redistribution into tissues.

Consequences of redistribution

• Termination of drug action: Thiopental is the textbook example. After a single IV bolus, it produces rapid anesthesia by concentrating in the brain. Within minutes, it redistributes into muscle and fat, and the patient wakes up. The drug hasn't been eliminated; it has just moved to a different compartment.
• Prolonged duration of action: Diazepam redistributes into fat and is then slowly released, contributing to its long duration of effect.
• Delayed toxicity: Drugs stored in fat or bone (chloroquine, lead) can be released slowly over time, causing toxicity long after the initial exposure.
• Altered pharmacokinetic parameters: Redistribution affects the apparent $V_d$ and elimination half-life, which has practical implications for dosing.

Barriers to drug distribution

Several anatomical structures act as selective barriers, restricting drug access to specific compartments. These barriers protect sensitive tissues but also create challenges for drug delivery.

Blood-brain barrier

The BBB is the most clinically significant distribution barrier. Its key features:

• Tight junctions between brain capillary endothelial cells eliminate paracellular transport
• Efflux transporters (especially P-glycoprotein) actively pump substrates back into the blood
• Lack of fenestrations in brain capillaries, unlike most other capillary beds
• Lipophilic, small, unionized molecules cross most readily

Pathological disruption (meningitis, tumors, stroke) can increase BBB permeability, sometimes allowing drugs to reach the CNS that normally wouldn't.

Blood-testis barrier

Formed by tight junctions between Sertoli cells in the seminiferous tubules. This barrier protects developing germ cells from drugs and toxins, which is important for maintaining fertility but can limit treatment of testicular infections or cancers.

Some molecules like testosterone and FSH can cross this barrier to support spermatogenesis.

Blood-placenta barrier

The syncytiotrophoblast layer of the placenta separates maternal and fetal circulations. It regulates nutrient and drug transfer to the fetus.

Lipophilic, unionized, low-molecular-weight drugs cross more easily. This has critical clinical implications: drugs like thalidomide and isotretinoin cross the placenta and are known teratogens, which is why they're absolutely contraindicated in pregnancy.

Physicochemical properties vs. barriers

The same drug properties that govern general distribution also determine barrier penetration:

• Lipophilicity: Higher lipophilicity = easier barrier crossing (partitions into lipid membranes)
• Molecular size: Molecules under ~400-500 Da cross more readily
• Ionization: Unionized forms are more lipophilic and cross barriers more easily (governed by the drug's $pK_a$ and the local pH)
• Protein binding: Only the free fraction can cross barriers, so highly bound drugs have limited penetration

Pharmacokinetic models

Pharmacokinetic models are mathematical frameworks that describe how drug concentrations change over time in the body. They're used to predict drug behavior and guide dosing decisions.

One-compartment model

The simplest model. It treats the entire body as a single, well-mixed compartment where the drug distributes instantaneously and uniformly.

• Drug elimination follows first-order kinetics: a constant fraction (not amount) is eliminated per unit time
• Characterized by a single $V_d$ and a single elimination rate constant ($k_e$)
• The plasma concentration declines as a single exponential: $C(t) = C_0 \cdot e^{-k_e t}$
• Works well for drugs that distribute rapidly and have simple elimination, like aspirin and ethanol

Two-compartment model

Divides the body into a central compartment (plasma and highly perfused organs) and a peripheral compartment (less perfused tissues like muscle and fat).

• After administration, there's an initial rapid decline in plasma concentration (the distribution phase, or $\alpha$ phase) as drug moves into the peripheral compartment
• This is followed by a slower decline (the elimination phase, or $\beta$ phase) as drug is cleared from the body
• Characterized by two volumes of distribution and two rate constants
• Appropriate for drugs like digoxin and gentamicin that show a clear two-phase decline in plasma concentration

Multi-compartment models

These extend the two-compartment approach by adding compartments for specific tissues or organs. Physiologically based pharmacokinetic (PBPK) models are the most detailed version, incorporating actual anatomical volumes, blood flows, and tissue-specific partition coefficients.

PBPK models are increasingly used in drug development to predict drug behavior across different populations (pediatric, geriatric, organ impairment) but require extensive data and computational resources.

Noncompartmental analysis

A model-independent approach that doesn't assume any specific compartmental structure. Instead, it calculates pharmacokinetic parameters directly from observed concentration-time data.

Key parameters derived from noncompartmental analysis:

• AUC (area under the curve): Total drug exposure over time
• Clearance (CL): $CL = \frac{\text{Dose}}{AUC}$
• Mean residence time (MRT): Average time a drug molecule spends in the body

This approach is useful when the distribution pattern is complex or when you don't have enough data to fit a compartmental model reliably.