Physiological pharmacokinetic models, often called flow-limited or perfusion models, typically assume a swift drug distribution between tissue and venous blood, creating a rapid drug equilibrium. This premise is based on the idea that drug diffusion is extremely fast, and the cell membrane presents no barrier to drug permeation. In this scenario, where no drug binding occurs, the drug concentration in the tissue equals that of the venous blood leaving the tissue. This greatly simplifies the related mathematics and allows for straightforward mathematical modeling. These models have been used to realistically describe drugs with high membrane permeability and minimal tissue binding, such as small lipophilic molecules like propranolol and fentanyl. They are ideal for analyzing drugs where blood flow is the primary determinant of tissue drug concentration. These models also have applications in drug discovery and development.

A more complex variant is the diffusion-limited or membrane-limited model. Here, the cell membrane acts as a barrier, gradually causing the drug to permeate through diffusion. A drug concentration gradient forms between the tissue and the venous blood due to the rapid blood flow and slow drug permeation. The rate-limiting step for drug diffusion into the tissue depends more on cell membrane permeation than blood flow. These models are more realistic for drugs with low membrane permeability or extensive tissue binding, such as digoxin and gentamicin. They provide detailed insights into the delayed equilibration between blood and tissue. However, this model's complexity arises from the time lag in equilibration between blood and tissue, making the pharmacokinetic equation for the diffusion-limited model quite intricate.

The choice of model depends on the drug's physicochemical properties and the specific pharmacokinetic questions being addressed. Flow-limited models suit drugs with rapid distribution, while diffusion-limited models are better for drugs with slow tissue permeation.