Distribution

Principles of Drug Therapy

## Pharmacokinetics: Drug Distribution

Definition: Drug distribution refers to the dispersion or spreading of substances throughout the fluids and tissues of the body.
After absorption or systemic administration, a drug distributes into the:
- Interstitial Fluid (ISF)
- Intracellular Fluid (ICF)
It is noteworthy that most drugs are not uniformly distributed throughout Total Body Water (TBW).
Certain drugs are restricted to:
- Extracellular Fluid (ECF)
- Plasma compartment

Lipid Solubility:
- A predominant factor influencing the extent of drug distribution, especially to the brain.
- The blood-brain barrier (BBB) restricts the penetration of polar and ionized molecules, complicating the entrance of certain drugs.

Initial Phase: Well-perfused organs such as the liver, kidney, and brain receive most of the drug rapidly.
Secondary Phase: Distribution to muscle, viscera, skin, and fat is slower; this phase may take minutes to several hours to reach equilibrium between blood and tissues.
- Sub-factors affecting this include:
  - Regional blood flow
  - Capillary permeability
  - Tissue predilection (affinity)
  - Tissue volume
  - Rate of delivery and amount of drug distributed into tissues

Drugs interact with plasma proteins and tissue macromolecules, which limit their distribution.
Factors Influencing Distribution:
- Molecular size: Large molecules (e.g., anticoagulant heparin) are largely confined to the plasma compartment.
- Drug binding status:
  - Free form (not bound to proteins)
  - Bound form (attached to plasma proteins)
- Types of interactions influencing binding:
  - Binding with tissue molecules
  - Capillary permeability
  - Binding with Plasma Proteins (PPB)

Certain drugs undergo active transport into cells:
- Example: Active transport into hepatic cells where enzymatic biotransformation occurs.
- In the intestines, drug transport can occur through P-glycoprotein (P-gp) from blood to lumen, which also exports many drugs from tissues (including anticancer agents).
- Inhibition of P-gp by drugs like amiodarone or erythromycin can increase tissue levels of transported drugs, enhancing their pharmacologic effects.
CNS Penetration: Some drugs penetrate into the Central Nervous System (CNS) via specific nutrient and compound uptake transporters.

Low drug concentrations exist due to the activity of efflux transporters (e.g., P-gp, MDR1, OATP).
Examples of drugs affected by efflux transporters include:
- HIV protease inhibitors
- Loperamide, an opioid lacking central effects.
Factors affecting export from the brain include the presence of OATP isoforms and their polymorphisms.

Reversible Binding: Drugs can oscillate between bound and free states based on equilibrium dynamics.
- As free drug diffuses into ISF and ICF, bound drugs dissociate from plasma proteins to maintain balance.
PPB dynamics are:
- Saturation: When higher affinity drugs displace lower affinity drugs from binding sites.

Drugs competing for PPB can impact the availability and effect of other drugs.
Measurement relationships are critical for those drugs that depend on free plasma concentration for effect (e.g., anti-arrhythmics).
- Changes in concentration ratios of free forms can influence:
  - Effect and elimination rates
  - Potential for rapid, short-lived effects
Liver and Kidney Roles:
- The liver synthesizes most plasma proteins which can be affected by conditions like liver disease or nephrotic syndrome, leading to hypoalbuminemia.

Drug transport and metabolism are limited by binding to plasma proteins, affecting tissue concentration and site of action.
- Only unbound drugs are in equilibrium across biological membranes.
Renal Filtration: PPB limits glomerular filtration but may not affect tubular secretion or biotransformation processes.
- The dissociation of the bound drug maintains the concentration balance post-processing.

Drug transfer across the placenta is critical due to potential fetal anomalies.
- When administered prior to delivery (e.g., tocolytics for preterm labor), drugs may adversely affect the neonate.
Key determinants of placental drug transfer:
- Lipid solubility
- Degree of plasma binding
- Ionization level
Fetal plasma has a slightly more acidic environment (pH 7.0-7.2 compared to maternal pH 7.4), affecting ion trapping of basic drugs.
Export transporters, including P-gp, protect the fetus from harmful substances, but some influx transporters allow drug exposure to the fetus.

Definition: The volume of distribution (Vd) quantifies the fluid volume required for a drug to match plasma concentration.
- It does not correlate to a specific body fluid compartment.
- Formula: (V_d = \frac{Dose}{Plasma\ volume})
Interpreting Vd:
- A low Vd suggests limited distribution to plasma or ECF (e.g., Warfarin has a Vd of about 8 L or 0.14 L/kg).
- A large Vd may indicate intracellular concentration, hence low plasma levels (Vd \gtrsim 5 L/kg indicates large Vd; Vd \lesssim 0.6 L/kg suggests small Vd).