Pharmacology: Drug Distribution in Body Fluids

Drug Distribution in Bodily Fluid Compartments

• Body water comprises 50-70% of body weight, varying between genders
• Extracellular fluid (ECF) includes blood plasma (4.5%), interstitial fluid (16%), and lymph (1.2%)
• Intracellular fluid (ICF) constitutes 30-40% body water
• Transcellular fluid (2.5%) encompasses various specialized compartments (e.g., cerebrospinal, intraocular, peritoneal, pleural, synovial, digestive secretions)
• Drugs exist in both free and bound forms within compartments
• Drug distribution in aqueous compartments is influenced by fluid pH and drug pK.
• Interstitial fluid accounts for ~16% of total body water
• Intracellular fluid accounts for ~35% of total body water
• Plasma water accounts for ~5% of total body water
• Transcellular water accounts for ~2% of total body water
• Fat tissues compose ~20% of total body water
• Bound drug molecules are associated with proteins or other components
• Free drug molecules are unbound and can move through different compartments
• Drug distribution is influenced by the presence of specific transport mechanisms

The Blood-Brain Barrier (BBB)

• Introduced by Paul Ehrlich to explain a dye's inability to stain the brain after injection
• Composed of continuous endothelial cells with tight junctions encircled by pericytes
• Efflux pumps actively transport molecules, including drugs, out of the CNS, limiting access to the central nervous system.
• Drugs with low lipid solubility typically struggle to penetrate the BBB
• Efforts to improve CNS drug delivery often focus on altering permeability proteins
• Inflammation can compromise BBB integrity and efflux pump activity
• Specific drugs (e.g., penicillin) might be preferred for intravenous administration over intrathecal use in cases with significant inflammation

Volume of Distribution

• Defined as the volume that would contain the total body content of a drug at the same concentration as in plasma
• Mathematically represented as Vd = Q/Cp (where Q = total body content of the drug, Cp = drug concentration in plasma)
• It's important to avoid directly equating Vd with a specific body compartment.
• Some drugs act at low concentrations, affecting receptors in various tissues (e.g., insulin acting on muscle, fat, and liver via interstitial fluid access, not just blood plasma)

Drugs Confined to the Plasma Compartment

• Plasma volume is approximately 0.05 L/kg of body weight
• Certain drugs, like heparin, remain primarily confined to the plasma due to their large size or strong binding to plasma proteins
• Pharmacological effects can arise even in cases of plasma binding; free drug in interstitial fluid can still exert therapeutic effects
• Repeated dosing can result in equilibrium, leading to higher measured volume of distribution.
• Certain dyes, like Evan's blue, bind strongly to plasma albumin, allowing for measurement of plasma volume
• Class 1 drugs: Drug dose is less than the binding capacity of plasma albumin, resulting in lower dose/capacity ratio with most drug bound and less free drug
• Class 2 drugs: Drug dose is more than the binding capacity of plasma albumin, resulting in higher dose/capacity ratio with a significant amount of free drug

Drugs Confined in the Extracellular Compartment

• Extracellular volume is roughly 0.2 L/kg body weight
• Polar compounds (e.g., vecuronium, gentamicin, carbenicillin) typically have volumes of distribution closely resembling that of extracellular volume due to limited lipid solubility, thus their limited ability to cross cell membranes.
• Macromolecular biopharmaceuticals, such as monoclonal antibodies, distribute in extracellular space but generally do not readily penetrate into cells.
• Nucleic acid-based biologics are often intracellular, requiring specialized delivery.

Drugs Confined to the Total Body Compartment

• Total body volume roughly equals 0.55 L/kg
• Drugs readily crossing cellular membranes (e.g., phenytoin, ethanol) frequently have volumes of distribution that are close to the total body water volume
• Factors like drug binding outside plasma and partitioning into body fat can increase Vd
• Certain drugs, including morphine, tricyclic antidepressants (TCAs), and haloperidol exceed total body volume
• Haemodialysis may prove ineffective at removing drugs exceeding total body volume, as it mostly filters blood plasma

Drug Interactions Caused by Altered Absorption

• Gastrointestinal absorption can be modulated by drugs that influence gastric emptying (e.g., atropine, metoclopramide)
• Drug interactions that affect absorption frequently involve changes in drug solubility or formation of drug complexes with dietary components (e.g., tetracycline’s reduced absorption in the presence of calcium or iron)
• Physiological factors affecting absorption include vasoconstriction (e.g., adrenaline added to local anaesthetics), which can delay absorption
• Pharmacodynamic modelling aids in predicting how genetic polymorphisms in drug transporters and their associated interactions with other drugs affect absorption

Drug Interactions Through Alteration of Distribution

• Drugs may compete for binding sites on plasma proteins or tissue proteins, leading to displacement
• Displacement of a drug can temporarily raise free drug concentration before elimination, resulting in a new steady state with similar free drug concentrations but a different overall total drug concentration
• Drug interactions involving alterations in distribution can have clinical significance
• Dose adjustments may be necessary for co-administered drugs, particularly when considering their impact on free drug concentrations and elimination.

Altered Distribution Because of Competition for Shared Transporters

• Drug competition involving shared drug transporters (e.g., SLC and ABC transporters) can alter drug distribution, affecting absorption, excretion, and metabolism.
• Drugs can compete for transport mechanisms, leading to altered pharmacokinetics
• Examples include Organic Anion Transporters (OATs) affecting drug distribution to the CNS (e.g., penicillin).
• New approaches to predict transporter interactions frequently utilize endogenous substrates as biomarkers for transporter function to improve the understanding and prediction accuracy of drug interactions involving transporter mechanisms

Special Drug Delivery Systems

• Pro-drugs, antibody-drug conjugates, and packaging in liposomes are examples of strategies to improve the delivery and efficacy of medications.
• Coated implantable devices provide a controlled release of drugs.

Pro-drugs

• Inactive precursors are metabolised into active forms within the body
• Examples of pro-drugs include cyclophosphamide, zidovudine, levodopa, and valaciclovir, and others
• Pro-drug delivery systems may provide advantages, like enhanced tolerability, targeted delivery, or reduced side effects.

Antibody-Drug Conjugates

• Combines a monoclonal antibody with a cytotoxic drug to target specific cancer cells
• Examples include ado-trastuzumab emtansine, brentuximab vedotin, and others.
• Improving selectivity of cytotoxic agents against cancer cells.

Packaging in Liposomes

• Drug encapsulation within liposomes (e.g., amphotericin B, doxorubicin) can enhance drug delivery.
• Modified liposomes can enhance delivery in certain applications

Coated Implantable Devices

• Used for drugs that may be delivered locally
• Coated stents deliver agents to prevent re-stenosis or in other applications
• Examples of implantable devices include intrauterine devices and stents.