Pharmacokinetics: Drug Distribution

Physiochemical Properties Affecting Drug Distribution

  • Drug distribution throughout the body is not equal and depends on various factors:

    • Drug Factors:

    • Molecular Weight (MW)

    • Lipid Solubility

    • Drug Binding Characteristics (Plasma Proteins)

    • Plasma Proteins:

    • Albumin for acid drugs

    • α-1 acid glycoprotein for base drugs

    • Tissue Factors:

    • pKa of the drug

    • pH of the distributing fluid

Molecular Weight Influence

  • Low Molecular Weight: Cross membranes easily.

  • High Molecular Weight: Struggle to cross membranes, remaining largely within plasma (e.g., monoclonal antibodies and protein-bound drugs).

Solubility Influence

  • Lipid Soluble, Nonionized Drugs: Easily penetrate and distribute across membranes.

  • Water Soluble, Ionized Drugs: Face difficulties crossing membranes and generally stay in plasma and interstitial fluid.

pKa and pH Considerations

  • Blood is normally slightly alkaline (average pH: 7.35-7.45).

  • Acidic Drugs (low pKa): Mostly ionized; do not cross membranes readily.

  • Basic Drugs (low pKa): Mostly nonionized; readily cross membranes.

Plasma Protein Binding Factors

  • Major Proteins:

    • Albumin: Binds acids

    • α-1 Acid Glycoprotein: Binds bases

  • Only unbound (free) drugs are biologically active and capable of crossing membranes. Bound drugs function as reservoirs, dissociating to maintain equilibrium as free drug concentration declines.

Principles of Drug Transport Across Membranes

  • Drug initially distributes from plasma into interstitial fluid (extracellular fluid).

  • The drug can then traverse biological membranes to infiltrate intracellular fluid and access protected tissues.

  • Key Determinants of Drug Movement:

    • Plasma protein binding is pivotal in drug distribution to interstitial fluid.

    • After reaching interstitial fluid, the primary determinant of drug movement into cells or secured sites is lipophilicity.

Protected Tissues Overview

  • Blood-Brain Barrier (BBB): Features tight junctions and specialized components (pericytes, astrocyte foot processes), necessitating drug transit through cells.

  • Requirements for Passage: Drugs must be lipid-soluble, nonionized, and unbound to cross the BBB.

  • P-glycoprotein Efflux Pumps: Active transport mechanisms at the BBB that expel drugs (e.g., MDR1 Mutation in Dogs can lead to toxicity due to drug accumulation).

  • Other Protected Sites: Eyes, Prostate, Placenta, Alveoli.

  • Impact of Inflammation: Inflammation can enhance drug permeation and increase protein concentration, affecting overall drug concentrations at protected sites for lipid-soluble, nonionized, unbound drugs.

Volume of Distribution (Vd)

  • Definition: Theoretical volume of fluid in which a drug appears to distribute.

  • Volume of Distribution (Vd) Equation: Vd=DCpVd = \frac{D}{Cp}

    • $D$: Dose

    • $Cp$: Plasma concentration

  • A higher dose resulting in lower plasma concentrations indicates a larger Vd, illustrating how extensively a drug distributes outside of plasma.

  • Vd is critical for selecting a drug targeting the desired site of action.

  • Vd calculation must be derived from an intravenous (IV) dose for accurate representation.

Vd Implications for Drug Treatment

  • Small Vd (0.05 L/kg):

    • Infers drug retention within plasma.

    • Treats diseases confined to plasma (e.g., Heparin, monoclonal antibodies).

  • Moderate Vd (0.1-0.3 L/kg):

    • Indicates retention within plasma and ISF.

    • Used by drugs like Penicillin, Gentamicin, and Cefovecin (Convenia®).

  • Large Vd (>0.6 - 1 L/kg):

    • Suggests widespread distribution in and outside the plasma (e.g., Enrofloxacin (Baytril®) with a Vd of 7 L/kg treating multiple sites).

Age Differences in Volume of Distribution
Age Impact

  • Neonates:

    • Increased body water content leads to larger Vd and lower plasma concentrations for water-soluble drugs.

    • Low fat content leads to smaller Vd and consequently higher plasma concentrations for fat-soluble drugs.

    • Total Body Water (TBW) for neonates: 85% (33% extracellular, 52% intracellular).

  • Older individuals:

    • Reduced body water content results in smaller Vd and higher plasma concentrations for water-soluble drugs.

  • Obese animals:

    • High fat content, resulting in larger Vd and lower plasma concentrations for fat-soluble drugs.

Disease Effects on Volume of Distribution

  • Dehydration:

    • Less fluid, raising plasma concentrations of water-soluble drugs.

  • Fluid Accumulation Conditions (e.g., cardiac and renal disease):

    • Promote fluid accumulation enhancing distribution of water-soluble drugs (larger Vd).

    • Lipid-soluble drugs may not distribute effectively, leading to higher plasma concentrations (smaller Vd) requiring dosing adjustments based on lean body mass.

  • Conditions Causing Protein Loss (e.g., protein-losing enteropathy/nephropathy):

    • Loss of albumin, or increases in proteins like alpha-1 AGP due to inflammation, can alter drug-binding availability, though typically with minimal clinical effect on Vd.