After drug administration, it is distributed through the vascular system to all parts of the body. So, the drug is distributed to all tissues, leaving only a fraction of the administered dose in the vascular system. Because it is not practical to determine the drug concentration in tissues, the vascular system (blood) represents an easy accessible sampling compartment.

When the drug is distributed extensively to tissues (large Vd), only a small fraction of the administered dose will remain in the sampling compartment (blood), and the blood drug concentration will be very low. On the other hand, if the drug is not distributed to tissues to a large extent (small Vd), large fraction of the administered dose will remain in the sampling compartment (blood), and the blood drug concentration will be large.

After drug administration, the drug is not distributed equally to all tissues. The extent of tissue distribution is dependent on the affinity of the drug to the tissue. Higher tissue:plasma partition coefficient means higher affinity of the drug to the tissue and larger volume of distribution.

The tissue:plasma partition coefficient for a drug depends on the physiochemical properties of the drug and the tissue characteristics. Because of these two factors, the same drug is not distributed equally to all tissues. Also, different drugs are distributed to the same tissue to different extents.

Drugs have different volumes of distribution because they have different physiochemical properties. These physiochemical properties affect the drug affinity to different tissues and the tissue distribution characteristics.

Examples:

- Highly lipophilic drugs are distributed readily to fatty tissues, while hydrophilic drugs are not.

- Lipophilic drugs can cross the blood brain barrier (BBB) and distribute to the brain, while hydrophilic drugs cannot cross the BBB.

- Highly hydrophilic drugs are distributed mainly to the extracellular space, and are not distributed to fatty tissues.