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Physiological barriers are semi-permeable structures that control drug movement into tissues and cells. The six primary barriers are the blood endothelial barrier, cell membrane, blood-brain barrier, blood-cerebrospinal fluid barrier, blood-placental barrier, and blood-testis barrier. Each barrier has distinct permeability properties that determine which drugs can cross based on size, lipophilicity, and transport mechanisms.

The vascular endothelium is highly permeable to most drugs, including ionized, un-ionized, and lipophilic molecules smaller than 600 Daltons. In contrast, the blood-brain barrier consists of brain capillaries with tight junctions between endothelial cells, making it impervious to non-lipophilic drugs. Only lipophilic molecules and drugs transported actively by carrier proteins can cross the blood-brain barrier.

Drugs cross cell membranes through three primary mechanisms. Lipophilic drugs and small molecules permeate easily through passive diffusion across the lipid bilayer. Larger or hydrophilic molecules require active transport via carrier proteins. The specific mechanism depends on drug size, chemical properties, and the availability of transport proteins in the cell membrane.

The blood-placental barrier consists of multiple layers of trophoblast cells that are less tightly joined than brain capillaries. It allows lipophilic molecules smaller than 1000 Daltons to pass into fetal circulation by passive diffusion, including barbiturates, anesthetics, antibiotics, and steroids. This reduced barrier function exposes the fetus to potential teratogens, requiring drug restriction during pregnancy.

Tight junctions are continuous connections between endothelial cells that prevent drug diffusion between cells. The blood-brain barrier and blood-cerebrospinal fluid barrier both feature tight junctions that block most hydrophilic substances from passing. These junctions force drugs to cross through cells rather than between them, creating a highly selective barrier that only permits lipophilic drugs or those actively transported by specific carrier proteins.

The vascular endothelium freely permits most drugs smaller than 600 Daltons to cross into extracellular fluid, regardless of whether they are ionized, un-ionized, or lipophilic. Larger complexes, such as drugs bound to plasma proteins, are excluded from crossing the endothelial barrier. This size cutoff allows rapid distribution of most therapeutic drugs from capillaries into tissues.

The blood-testis barrier is formed by neighboring Sertoli cells joined by tight junctions that restrict drug diffusion from capillaries into the testis. This barrier protects spermatids from drug exposure by preventing most molecules from entering the testicular tissue. Like the blood-brain barrier, it creates a specialized microenvironment with limited drug accessibility.