PK – Distribution

Master answer

Definition

Volume of Distribution (Vd) = The theoretical volume of bodily fluid in which a drug would need to be distributed following its administration to produce the observed / desired plasma concentration

Mathematically, at time t=0:

Factors Influencing Volume of Distribution

Drug factors

• ↑ Plasma protein binding
  • ↓’s Vd
• ↑ Tissue binding
  • Binds to tissues  → ↓ circulating drug → apparent ↑ Vd
• Physicochemical properties of drug
  • ↑ Lipophilicity → ↑ Vd
  • ↑ Hydrophilicity → ↓Vd
  • ↓ Size → ↑ Vd
  • ↓ Charge → ↑ Vd
  • pKa
    • Basic drug → lower pKa = ↑ unionised portion → ↑ Vd
    • Acidic drug → higher pKa = ↑ unionised portion → ↑ Vd

Patient factors

• ↓ pH → ↑’d ionisation of basic drugs → ↓ diffusion → ↓ Vd
• Blood flow
  • ↑ blood flow → ↓d concentration → ↑ Vd
• Age
  • ↑ Vd in neonates
• Total body water ↑ with
  • ↓ age (neonates highest)
  • Male gender
  • ↑ volume of distribution for water soluble drugs.
• total body fat
  • ↓’d in children and men → ↓ Vd of lipophillic drugs
• skeletal muscle bulk
  • ↑’d in men → ↑ Vd
• disease
  • Sepsis: alterations in pH alter ionised and bound fractions of drugs, increased permeability, organ failure and acute phase reactants all alter protein binding and Vd.

Measurement of Volume of Distribution

It is calculated based on the formula:

Since it is impossible to measure plasma concentration at time zero, an extrapolated plasma concentration is used.

Semilogarithmic plot above illustrates extrapolation of plasma level to time 0 required to determine the volume of distribution

This graph applied for a single compartment model only.

For multiple compartments which will appear as a non-linear relationship, extrapolation back to t = 0 must be performed for each compartment separately.

Gladwin / JC 2019

Answer by Gladwin, JC