Drug Distribution in the Body
How drugs travel from the bloodstream into tissues, and the factors that determine where drugs accumulate in the body.
From Blood to Tissues
After reaching the systemic circulation, a drug distributes throughout the body. Distribution is not uniform — drugs concentrate in certain tissues based on blood flow, membrane permeability, protein binding, and tissue affinity.
Protein Binding
In plasma, drugs bind reversibly to proteins — primarily albumin (acidic drugs) and alpha-1-acid glycoprotein (basic drugs). Only the free (unbound) fraction is pharmacologically active because bound drug cannot cross membranes or interact with receptors.
Clinically significant protein binding:
- Warfarin: 99% bound; a small displacement (99% to 98%) doubles the free fraction
- Phenytoin: ~90% bound; hypoalbuminemia in cirrhosis or nephrotic syndrome increases free drug and toxicity risk
- Diazepam: ~98% bound to albumin
Protein binding displacement rarely causes sustained clinical effects because increased free drug is quickly redistributed and eliminated, reaching a new equilibrium.
Tissue Barriers
Several specialized barriers restrict drug access:
- Blood-brain barrier (BBB): Tight junctions between endothelial cells exclude most polar and large molecules. Only lipophilic, un-ionized drugs (e.g., diazepam, fentanyl) cross readily. Inflammation can transiently increase BBB permeability.
- Placental barrier: Not a true barrier — most drugs cross by passive diffusion. Molecular weight, lipophilicity, and protein binding influence transfer rate.
- Blood-testis barrier: Sertoli cell tight junctions limit drug penetration, complicating treatment of testicular infections.
Factors Governing Distribution
| Factor | Effect |
|---|---|
| Cardiac output | Higher output delivers drug to tissues faster |
| Regional blood flow | Highly perfused organs (brain, liver, kidney) receive drug first |
| Capillary permeability | Fenestrated capillaries (liver) allow large molecules; tight capillaries (brain) restrict them |
| Tissue binding | Lipophilic drugs accumulate in adipose tissue (thiopental) |
| Lipophilicity | Determines membrane crossing and tissue uptake |
Redistribution
Highly lipophilic drugs like thiopental initially concentrate in the well-perfused brain, causing rapid anesthesia. Within minutes, the drug redistributes into less-perfused muscle and fat, and consciousness returns — even before significant elimination occurs.
Key Takeaways
- Only free (unbound) drug is pharmacologically active
- The BBB, placenta, and blood-testis barrier selectively restrict drug access
- Cardiac output and regional blood flow determine initial distribution
- Redistribution from well-perfused to poorly-perfused tissues can terminate drug effect before elimination