Distribution

Distribution in Pharmacokinetics

Distribution is the second step in the pharmacokinetic process describing the movement of drug around the body and into the various tissues. Distribution is the step that delivers drug to its site of action, whether that's deep within the cells of a specific organ or inside the blood. The extent and pattern of drug distribution depends largely on physiological factors like blood flow and tissue permeability, and interactions occurring between the drug and plasma proteins and tissue components.

At the conclusion of the absorption phase, drug has entered the systemic circulation. But it does not remain confined to the bloodstream. During the distribution phase, drug molecules will begin to move into various tissues and organs throughout the body. This distribution occurs through diffusion across capillary walls and cellular membranes, driven by concentration gradients in much the same way as in Absorption.

Volume of Distribution (V_d)

The volume of distribution (V_d, V_dist) is a pharmacokinetic parameter that relates the amount of drug in the body to the concentration of drug in the plasma. It is not a true volume that can be found anywhere in the body but rather it represents the theoretical volume of fluid (in litres or L/kg body weight) that would be required to dilute the administered dose down to the concentration observed in the plasma. This arises from the fact that it is relatively easy to determine concentrations of drug that are remaining in the plasma but relatively difficult to determine the drug concentrations in other tissues (such as inside the brain). It is a useful pharmacokinetic parameter because it tells us whether drug is mostly staying in the blood (when V_d is small) or distributing out of the blood and into other tissues (when V_d is large). V_d is given by the following equation.

$$ V_d = \frac{amount\ of\ drug\ in\ body}{plasma\ drug\ concentration} $$

Interpreting V_d Values

V_d values can range from as small as 3–5 L (confined mainly to plasma) to several thousand litres (extensively distributed to peripheral tissues). Understanding what these values indicate is essential for predicting drug behaviour.

The body contains about 3–5 L of water within the blood and this is the absolute minimum V_d theoretically possible. Drugs with small V_d (<15 L or <0.2 L/kg) are largely confined to the vascular compartment and extracellular fluid. These drugs typically have features that cause them to be restrained within this central compartment: high molecular weight, highly bound to proteins in plasma, highly hydrophilic, charge at physiological pH (~7.4). Examples include heparin (V_d ~5 L), warfarin (V_d ~8 L), and gentamicin (V_d ~15 L). These drugs remain mostly in the blood and don't move out into peripheral tissues much.

Drugs with large V_d (>50 L or >0.7 L/kg) exhibit extensive binding to components of tissue. A V_d that appears to exceed total body water indicates the drug concentrates in tissues at higher levels than in plasma. These drugs are typically highly lipophilic, allowing extensive tissue penetration and they probably have a high affinity for something in the tissue (eg fat in adipose tissue, protein in muscle). Examples include chloroquine (V_d ~15,000 L), digoxin (V_d ~500 L), and amiodarone (V_d ~5,000 L).

Clinical Implications of V_d

V_d has several important clinical applications. First, it allows calculation of a large dose that can rapidly achieve a target plasma concentrations in one dose (termed a “loading dose”):

$$ loading\ dose = V_d \times C_{target} $$

where C_target is the desired plasma concentration (set within the therapeutic range of the drug). A drug with a large V_d requires a large loading dose because much of the administered dose will end up distributing into tissues, reducing plasma concentrations.

A second important clinical use of V_d is in poisonings and overdoses. Elimination procedures such as haemodialysis are effective at cleaning toxicants from the blood. This is excellent for low V_d drugs which are easy to remove by this method. High V_d drugs will be much more challenging as they exist mostly away from the blood. Alternative methods must be used for such substances.

Lysosomal Trapping

Lysosomal trapping is a passive physico-chemical mechanism by which weakly basic, lipophilic drugs accumulate within lysosomes. You may recall that weak bases are unionised at high pH but become ionised at low pH. Lysosomal trapping comes about because of the imbalance in pH between the neutral intracellular fluid (pH 7.0–7.2) and the slightly acidic interior of lysosomes (pH 4.5–5.0). Lipophilic amines are unionised in the cytosol and so diffuse freely across the lysosomal membrane but become protonated within the lysosomes acidic interior. Being charged, they can no longer diffuse across the lysosomal membrane—they are trapped! This ion-trapping mechanism results in intralysosmal drug concentrations much higher than in the cytoplasm. Drugs such as chloroquine, hydroxychloroquine, amiodarone, and many antidepressants (eg fluoxetine, amitriptyline) accumulate in lysosomes and give them their very large volumes of distribution (often hundreds of litres) and their prolonged tissue residence times. It also underlies the phospholipidosis caused by some of these agents, and explains why tissue-to-plasma ratios can be extremely high in organs rich in lysosomes, such as the liver and lungs.

Plasma Protein Binding

Normal plasma contains around 70 g/L of protein. When a drug enters the bloodstream, it many bind to these plasma proteins depending on the physicochemical properties of the drug and protein. Notable plasma proteins and their preferred drug ligands include...

Summary of important plasma proteins that can bind drugs.

Plasma protein	Abundance	Types of ligands	Drug examples
Albumin	55–60%	Acidic drugs	warfarin NSAIDs (eg ibuprofen, naproxen) Benzodiazepines Penicillins valproate, phenytoin
α-1-acid glycoprotein	~1%	Basic drugs	β-1-AR blockers (eg propranolol) local anaesthetics (eg lidocaine) Tricyclic antidepressants (eg imipramine, amitriptyline) erythromycin
Lipoproteins	~10%	Lipophilic drugs	Cannabinoids cyclosporin
Globulins (excluding lipoproteins)	25–28%	Specific molecules with endogenous analogues	Corticosteroids (eg dexamethasone, prednisolone) Hormonal replacement (eg levothyroxine, testosterone)

There is also a minor role of binding of some drugs to red blood cell components. Red blood cells are the most abundant cells in blood and their membranes present ample surface area for drug adsorption. Examples of drugs bound to red blood cell membranes include codeine, some antiparasitics (eg mefloquine, pyrimethamine), chlorpromazine and imipramine. Inside the red blood cell, many drugs can bind to haemoglobin, the carrier of oxygen. Examples include digoxin, sulfonamides, nitrofurantoin, mefloquine, phenothiazines (eg chlorpromazine), tricyclic antidepressants (eg imipramine), phenytoin, barbiturates, benzodiazepines and salicylates (eg aspirin). Also inside red blood cells is carbonic anhydrase, an enzyme involved in pH regulation of blood. Chlorthalidone and dorzolamide bind to this enzyme inside red blood cells.

Binding to any proteins in blood affects drug distribution, pharmacological activity, and elimination because while the drug molecule is bound to plasma protein, it cannot diffuse out of the blood, interact with its target, be metabolised by liver enzymes or be excreted in the kidneys.

The extent of protein binding is expressed as the fraction bound (f_b) or percentage bound. The binding between drug and protein follows the law of mass action:

$$ drug + protein \rightleftharpoons drug{\text -}protein\ complex $$

Binding (and unbinding) of drug to the plasma protein exists in equilibrium. The bound drug-protein complex is far too large to cross capillary membranes and move into tissues so the drug-protein is effectively trapped inside the vascular compartment until unbinding occurs.

The fraction of drug that is unbound (free) is denoted f_u: $$ f_u = 1 - f_b $$

For example, if a drug is 95% bound (f_b = 0.95), f_u = 0.05; only 5% of the drug in plasma can be considered pharmacologically active.

Albumin

Albumin is the most abundant plasma protein, with normal concentrations of 35-50 g/L (55–60% of total plasma protein). Physiological functions of albumin include maintaining oncotic pressure and transporting endogenous substances like bilirubin. Albumin also binds many drugs, particularly acidic and neutral drugs.

Albumin contains two primary drug-binding sites: Sudlow site I (the warfarin binding site) and Sudlow site II (the benzodiazepine binding site). Drugs competing for the same binding site can displace each other, potentially leading to drug interactions (discussed in Distribution Phase Drug Interactions).

Examples of drugs with high albumin binding include warfarin (~99%), phenytoin (~90%), valproic acid (~90%), and naproxen (~99%). Because albumin binding is so extensive for these drugs, small changes in binding (or changes in albumin concentration) can cause dramatic changes in free drug concentration and therefore drug efficacy. For instance, if warfarin binding decreases from 99% to 98%, the free fraction doubles from 1% to 2%, potentially doubling the pharmacological effect.

Albumin concentration is susceptible to changes during various conditions including liver disease (albumin is produced by the liver), nephrotic syndrome, malnutrition, burns and acute inflammation. Pregnancy also causes a decrease in albumin concentration during the third trimester due to dilution.

α-1-Acid Glycoprotein (AAG)

α-1-acid glycoprotein (AAG, orosomucoid), is an acute phase protein with normal plasma concentrations of 0.6-1.2 g/L—considerably lower than albumin. Despite its lower concentration, AAG is clinically important because it binds basic drugs and some neutral lipophilic drugs with high affinity.

As an acute phase protein, AAG concentrations increase 2–5x during infection, inflammation, myocardial infarction, surgery, trauma, and cancer. This increase can significantly affect the free fraction of drugs that bind to AAG.

Examples of drugs with high AAG binding include lidocaine (~70%), propranolol (~90%), imipramine (~90%), and erythromycin (~90%). When AAG increases during the conditions listed above, the plasma concentrations of these drugs can decrease signfiicantly.

Other Binding Proteins

While albumin and AAG are the major drug-binding proteins, several others play specialised roles. Lipoproteins bind highly lipophilic drugs like ciclosporin and cannabinoids. Transcortin (a corticosteroid-binding globulin) binds exogenous corticosteroids (eg prednisolone, dexamethasone). Sex hormone-binding globulin binds testosterone and oestrogens used in hormone replacement therapy and contraceptives. Thyroxine-binding globulin binds thyroid hormones. These proteins are generally less broad than albumin and AAG but can be important for specific drugs.

Distribution to Specific Tissues

Distribution to the Liver

Distribution of drugs into the liver (for both drug action and drug metabolism) is governed primarily by transporters on the basolateral (sinusoidal) membrane which faces the portal blood supply. The most clinically significant of these are OATP1B1, OATP1B3 and OATP2B1 which mediate sodium-independent uptake of a broad range of organic anions from portal blood into hepatocytes. Their substrates include most statins, bosentan, some chemotherapeutics (taxanes, methotrexate, vemurafinib, sorafenib), antiviral (maraviroc, presatovir), fexofenadine and endogenous compounds such as bilirubin and bile salts. Together, these OATPs are the principal mechanism by which the liver achieves its high first-pass extraction of many anionic drugs, and their activity largely explains the hepatic selectivity of drugs such as the statins—compounds deliberately designed to be concentrated in the liver where they exert their therapeutic action.

OCT1 handles organic cations at the basolateral membrane, with metformin as its most important substrate; hepatic OCT1 activity is a key determinant of metformin's intrahepatic concentration and therefore its pharmacodynamic effect. OAT2 contributes to basolateral uptake of organic anions including some antivirals and NSAIDs.

When hepatic elimination via bile is overwhelmed or impaired, the effluxers MRP3 and MRP4 on the basolateral membrane provide an overflow route, pumping drugs and their metabolites back into the sinusoidal blood to return to the systemic circulation. This is clinically relevant in cholestatic states, where upregulation of these transporters represents a hepatoprotective adaptation. Other hepatocyte basolateral efflux transporters include the organic solute transporters (OSTα and OSTβ) which are important for conjugates of steroid drugs. Members of the OAT/OCT families also act as efflux transporters if the concentration gradient of the drug/metabolite favours outward movement.

Distribution to the Kidneys

Active secretion of drugs into the urine requires active uptake of drug from the blood into the renal proximal tubular cells before they can be effluxed into the tubular lumen (filtrate). From a distribution perspective, the relevant renal transporters are on the basolateral membrane of proximal tubular cells, which extract drugs from the peritubular capillary blood.

For organic anions, the principal basolateral uptake transporters are OAT1 and OAT3 which extract anionic drugs from peritubular blood into the tubular cell. Classic substrates include loop diuretics (furosemide), methotrexate, penicillins, tenofovir and many non-steroidal anti-inflammatory drugs. OCT2 performs the equivalent function for organic cations, with metformin and cisplatin as representative substrates.

Basolateral MRP3 in the kidney can return drugs from tubular cells back into the peritubular circulation, broadly analogous to its hepatic role.

Distribution to the Brain

The blood-brain barrier (BBB) is formed by the tight junctions between cerebral endothelial cells. The transporter profile on these endothelial cells is heavily biased towards drug efflux.

Influx into the brain is mediated by several carrier transporters. LAT1 transports large neutral amino acids and is exploited by some clinically-important drugs—levodopa and gabapentin both gain entry to the CNS via the LAT1 transporter. MCT1 contributes to CNS distribution of monocarboxylates including valproate. OATP1A2 contributes to brain influx of opioids and some antiretrovirals from the luminal surface.

Acting to oppose uptake into the brain, several efflux transporters have strong expression at the BBB. The dominant efflux transporters are MDR1/P-gp and BCRP, both expressed on the luminal (blood-facing) membrane of cerebral endothelial cells, where they pump substrates back into the circulation before they can accumulate in brain tissue. P-gp substrates that are effectively excluded from the CNS include loperamide, many HIV protease inhibitors, and paclitaxel even though these drugs are physicochemically able to cross the BBB by passive diffusion. BCRP has substantial substrate overlap with P-gp, and the two transporters together create a highly redundant efflux barrier. MRP4 contributes additional luminal efflux, particularly for nucleotide-like drugs such as the antiviral agents (adefovir, tenofovir, ganciclovir) and anticancer drugs (methotrexate, 6-thioguanine, 6-mercaptopurine, topotecan and camptothecins).

Distribution to the Lungs

The lung deserves special mention as a distribution site. While it receives the entire cardiac output with every circuit, and is thus transiently exposed to very high drug concentrations, it is not generally a major reservoir compartment for most drugs. However, weakly basic lipophilic amines (the main example is amiodarone) accumulate extensively in lung tissue through the mechanism of lysosomal trapping and non-specific binding to phospholipids of the cell membranes. Consequently, the tissue concentrations of amiodarone in the lung can be several-fold higher than blood and contributes to its propensity to cause pulmonary toxicity.

Distribution to Adipose Tissue

Adipose tissue acts as a large-capacity, low-affinity reservoir for highly lipophilic drugs. Unlike other tissues such as liver or kidneys which take up drug by transporter actions, distribution into fat is driven by passive diffusion down a concentration gradient and is governed by the oil-water partition coefficient (logP) of the drug. Drugs with high logP values—including amiodarone, chlorpromazine, azole antifungals and organochloride pesticides such as DDT—partition extensively into adipose tissue. This process is entirely passive; there are no characterised drug transporters of clinical significance in adipocytes. The pharmacokinetic consequence of extreme LogP is a very large volume of distribution and prolonged terminal half-life. In obesity, the expanded adipose mass increases the volume of distribution for such drugs, which has practical dosing implications.

Distribution to Bone

Bone serves as a distribution sink for two notable drug classes. Bisphosphonates (alendronate, zoledronate) bind with extremely high affinity to bone mineral, achieving very high local concentrations and a biological half-life of several years. Tetracycline antibiotics (doxycycline, minocycline) similarly chelate calcium in mineralising bone and are contraindicated in children childhood and pregnant people.

Fraction Unbound (f_u)

The fraction unbound represents the proportion of total drug in plasma that exists in the free (unbound) state and is available for pharmacological activity and elimination. As mentioned above, f_u = 1 - f_b, where f_b is the fraction bound.

For drugs with high protein binding (>90%), small changes in binding can cause large changes in free concentration. Consider a drug that is 95% bound (f_u = 0.05). If total plasma concentration is 100 mg/L, free concentration is 5 mg/L. If binding decreases to 90% bound, f_u is now 0.10 and free concentration doubles to 10 mg/L, despite total concentration remaining 100 mg/L and f_b changing only slightly. This is why highly protein-bound drugs are more susceptible to clinically significant displacement interactions.

Clearance (CL)

Clearance is a fundamental parameter that reappears throughout pharmacokinetics. It represents the volume of plasma from which drug has been completely removed per unit time. While clearance is primarily driven by metabolism and excretion—the two physiological mechanisms of removing drug from the plasma—it profoundly affects distribution because it determines the steady-state concentration achieved for a given dosing rate. Clearance is expressed in volume per unit time (eg mL/min, L/h). A clearance of 100 mL/min means that 100 mL of plasma is completely cleared of drug every minute. Note that this doesn't mean 100 mL of plasma is processed; rather, drug is removed from a larger volume of plasma such that an equivalent of 100 mL is completely cleared.

$$ CL = \frac{rate\ of\ elimination}{plasma\ concentration} $$

A More Useful Equation for CL

A useful alternative equation for calculating clearance uses the administered dose and the area under the plasma concentration-time curve (AUC):

$$ CL = \frac{dose}{AUC} $$

For extravascular routes (eg oral), bioavailability must be included:

$$ CL = \frac{F \times dose}{AUC} $$

This equation is valuable because it allows clearance to be calculated from a known value (the dose) and an easily measured value (the total drug exposure, AUC). Let's see where this equation comes from...

Starting with the basic equation for clearance stated above, rearranged, we know that at any given time:

$$ rate\ of\ elimination = CL \times C $$

where C is the plasma concentration at that moment in time.

Now, the total amount of drug eliminated from the body can be found by integrating the rate of elimination over all time (from time 0 to time ∞):

$$ amount\ eliminated = \int_0^\infty rate\ of\ elimination \cdot dt = \int_0^\infty CL \times C \cdot dt $$

Since clearance is a constant for most drugs, we can factor CL out of the integral:

$$ amount\ eliminated = CL \times \int_0^\infty C \cdot dt $$

The integral ∫C·dt is, by definition, the area under the concentration-time curve (AUC). Therefore we can simplify to:

$$ amount\ eliminated = CL \times AUC $$

For drugs given intravenously (or peroral drugs with F=1.0), all of the administered dose mut eventually be eliminated from the body. Therefore, the amount eliminated equals the dose and we can simplify again:

$$ dose = CL \times AUC $$

Rearranging gives us:

$$ CL = \frac{dose}{AUC} $$

Note that above, I specified that this was true only for intravenous drugs which have complete bioavailability by definition. For peroral or other extravascular routes, only the bioavailable fraction of the dose (F × dose) reaches the systemic circulation and can be measured via AUC. Therefore...

$$ CL = \frac{F \times dose}{AUC} $$

Clearance at Steady State

At steady-state (when rate of drug input equals rate of drug elimination), clearance determines the steady-state plasma concentration:

$$ C_{ss} = \frac{dosing\ rate}{CL} = \frac{F \times dose}{CL \times \tau} $$

where τ is the dosing interval. Drugs with high clearance require higher dosing rates to maintain therapeutic concentrations, while drugs with low clearance accumulate to higher steady-state concentrations with the same dosing rate.

This equation also implies that changes in CL (eg due to a drug metabolism interaction or changes in kidney function), will also change the C_ss with inverse proportionality. If CL halves, C_ss can be expected to double. Similarly, dose is directly proportional to C_ss so doubling dose can be expected to double C_ss. Astute clinicians who pay close attention to their patient's kidney function will be able to preemptively make careful dosage adjustments to maintain a relatively consistent steady-state concentration.

Let us do an example. A patient is recieving drug A i.v at a dose of 100 mg regularly (assume steady-state). CL is 10 L/h and is 60% cleared by the kidneys and 40% non-renal clearance. If their kidney function declines to 25%, what should be their new dose to maintain C_ss? Renal CL (6 L/h) decreases to 1.5 L/h while non-renal CL (4 L/h) is unchanged so the new CL is 5.5 L/h. Therefore, their new dose should be 100 mg × (5.5 L/h / 10 L/h) = 55 mg!

Elimination

Clearance can be contrasted with a very similar concept “elimination”. Elimination is the amount of drug removed from the blood; clearance is the volume of blood from which drug has been removed. Clearance is measured in volume of drug per time (eg L/h, mL/min) whereas elimination is measured in amount of drug per time (eg mg/h, µmol/min). I think elimination is a much clearer concept but clearance is a much more useful parameter for clinical pharmacokinetics (as we will see soon).

Half-Life (t_½)

Half-life is the time required for the plasma concentration (or amount of drug in the body) to decrease by 50%. It's one of the most clinically useful pharmacokinetic parameters because it directly informs dosing interval decisions and predicts time to steady-state.

A Relationship Between Half-Life and Clearance

As we've discussed previously, clearance is the foremost factors that determines how long drug stays in the body. It is therefore linked closely to half-life,t_½.

$$ t_{½} = \frac{0.693 \times V_d}{CL} $$

This equation reveals that half-life is determined by both volume of distribution and clearance. A drug generally has a long half-life if clearance is poor due to one or more of 1) inefficient metabolic elimination, 2) inefficient excretion, 3) sequestration in tissues (high V_d) or bound to plasma (high f_b). Conversely, short half-lives may result from rapid metabolism and efficient excretion.

Extraction Ratio (E)

The extraction ratio represents the fraction of drug removed from blood during a single pass through an eliminating organ (usually the liver or kidneys). It is calculated as:

$$ E = \frac{C_{in} - C_{out}}{C_{in}} $$

where C_in is the concentration of drug in the artery that supplies the organ and C_out is the concentration in the vein that drains the organ.

Drugs may be described as having high (E >0.7), intermediate (E = 0.3–0.7), low (E < 0.3) or no (E = 0.0) extraction. Drugs with complete extraction (E = 1.0) are totally removed from the blood during a single pass through the organ.

Extraction ratio is important for a given organ because it is one of two determinants of clearance by that organ (the other being blood flow to the organ). For example, hepatic clearance is determined by the blood flow through the liver and the hepatic extraction ratio of the drug. The relationship between clearance, blood flow (Q), and extraction ratio is:

$$ CL = Q \times E $$

This equation shows that for drug with ample extraction ratio, clearance is flow-limited. Conversely for low extraction drugs, clearance is “capacity-limited”—the clearing organ may have plenty of time to clear the drug (ie due to low Q) but is limited by uptake from the blood, efficiency of metabolising enzymes, binding to plasma proteins etc.

We'll revisit extraction ratios as we try to understand clearance by hepatic biotransformation in Metabolism.

High Extraction Drugs

High extraction drugs are extensively removed during their first-pass through the liver. Examples include lignocaine (E = 0.7), propranolol (E = 0.7), morphine (E = 0.7), and verapamil (E = 0.9). For these drugs, hepatic clearance is almost equal to hepatic blood flow. Therefore, changes in liver blood flow will significantly affect clearance. For example, reduced hepatic blood flow decreases clearance and increases drug exposure. See the table below for more factors that influence hepatic blood flow.

Factors affecting hepatic blood flow.

Increased Hepatic Blood Flow	Decreased Hepatic Blood Flow
Increased cardiac output After meal Hypercapnia (↑CO2) and acidosis	Heart failure Fluid overload Exercise Shock Vasoconstrictors (eg vasopressin, adrenaline) Mechanical ventilation

High hepatic extraction ratio drugs often have poor oral bioavailability because they are efficiently removed from the blood by the liver on their first pass (ie before reaching the systemic circulation), a problem referred to as the “first pass effect”.

Low Extraction Drugs

Low extraction drugs are poorly extracted by the liver. Examples include warfarin (E = 0.03), phenytoin (E = 0.03), and diazepam (E = 0.03). For these drugs, clearance is limited by the unbound fraction and intrinsic metabolic capacity, not by blood flow. Changes in protein binding or enzyme activity significantly affect clearance, but changes in liver blood flow have minimal impact. These drugs typically have high oral bioavailability because little drug is removed during first-pass.

Factors Affecting Distribution

Physicochemical Properties

Since distribution to tissues requires diffusion across the membranes of capillary endothelial cells in much the same way as absorption, many of the same physicochemical properties discussed in Factors Affecting Absorption will also appear here.

As was the case for peroral absorption, lipophilicity may be the most important drug property affecting its distribution. Lipophilic drugs (high LogP) readily cross cell membranes and distribute extensively into tissues. In the distribution phase, lipophilicity has an additional effect in that certain target tissues are high in lipid (eg adipose tissue is high in triglycerides, the brain is high in cholesterol) and therefore attract high LogP drugs. Highly lipophilic drugs such as amiodarone, chloroquine, and haloperidol have very large volumes of distribution because they are so strongly attracted to these lipid-rich tissues (in contrast to the aqueous blood). Hydrophilic drugs (low LogP) have difficulty crossing lipid membranes and tend to remain in blood and extracellular fluid, resulting in smaller volumes of distribution.

Molecular size also affects distribution. Small molecules (<500 Da) can cross membranes more easily than large molecules. Very large molecules such as heparin (12,000-15,000 Da) cannot cross capillary membranes easily and remain largely confined to plasma.

Charge state influences distribution because ionised drugs have difficulty crossing lipid membranes. The pH-partition hypothesis states that drugs cross membranes only if they're in non-ionised form; charged drugs do not cross membranes. However, a mismatch between intracellular (pH 7.0) and extracellular (pH 7.4) creates an ion trapping effect. Weak bases are non-ionised in the relatively alkaline extracellular fluid, diffuse across the membrane and become ionised (trapped) inside the relatively acidic intracellular compartment. The inverse is true of weakly acidic drugs which accumulate in the extracellular compartment.

Tissue Blood Flow

Distribution occurs more rapidly to highly perfused tissues (heart, brain, liver, kidneys) than to poorly perfused tissues (muscle, fat, bone). This creates a biphasic distribution pattern: initial rapid distribution to highly perfused tissues (α-phase) followed by slower distribution to poorly perfused tissues (β-phase).

The distribution of cardiac output to different organs affects how quickly tissues equilibrate with plasma. The brain receives ~15% of cardiac output despite representing only ~2% of body weight, facilitating rapid CNS effects. Adipose tissue receives only ~3% of cardiac output despite representing 15-30% of body weight in normal individuals, causing slow accumulation of lipophilic drugs in fat.

Membrane Barriers

Certain anatomical sites have uniquely tight barriers that restrict drug distribution. They either strongly resist drug uptake into the tissue or efficiently efflux drugs back into the blood. These membrane barriers exist to protect vulnerable organs (eg brain, gonads) but can complicate drug delivery when these organs are diseased.

The endothelial cells of the capillaries traversing the brain have extremely tight junctions that strongly oppose paracellular transport of hydrophilic drug molecules. The blood–brain barrier (BBB) is generally only permeable to small, lipophilic, non-ionised molecules. The BBB also expresses efflux transporters like P-glycoprotein that actively pump some drugs out of the brain. These two features mean the central nervous system (CNS) is very difficult to reach with drugs. Inflammation, trauma or CNS infections can disrupt the BBB, increasing drug penetration. For example, cetriaxone, a relatively hydrophilic (LogP = -1.3) antibiotic for treating meningitis, can only penetrate an inflamed BBB (as is the case during meningitis).

The placental barrier partially restricts maternal drug transfer to the foetus, though most drugs eventually cross to some degree. Lipophilic drugs cross more readily than hydrophilic drugs. P-glycoprotein in the placenta provides some protection by effluxing certain drugs back into maternal circulation.

The blood–testis barrier protects developing sperm from blood-borne substances. The blood-retina barrier limits drug penetration into the eye, often necessitating local administration for ophthalmic infections or inflammation.

Tissue Binding

Many drugs bind to tissue components beyond plasma proteins. Digoxin binds to Na⁺/K⁺-ATPase in muscle, creating an enormous volume of distribution. Chloroquine accumulates in lysosomes through ion trapping, reaching concentrations in tissues 500-fold higher than plasma. Tetracyclines bind to calcium in bones and teeth, which is clinically significant in children and pregnant women. Heavy metals like lead accumulate in bone. This tissue binding can serve as a drug reservoir, prolonging duration of action as drug slowly releases from tissues back into plasma.

Quiz