Upon entering the systemic circulation, drugs can distribute into the interstitial and intracellular fluid of various tissue cells. This distribution is facilitated by the binding of drugs to different cellular components within tissues, which may lead to drug accumulation in specific areas. Drugs bound to tissue components serve as reservoirs that release free drugs back into the system, prolonging the drug's overall action. However, this accumulation can also result in local toxicity.

For instance, acrolein, a metabolic byproduct of cyclophosphamide, binds to renal tissues and accumulates within renal cells, causing nephrotoxic effects. Lipophilic drugs, on the other hand, tend to bind to body fat. Since fat is a poorly perfused tissue, it functions as a stable drug reservoir for these drugs. Additionally, bones can act as drug storage sites, as seen in the treatment of osteoporosis using alendronate therapy. In this case, the phosphonate binds to hydroxyapatite crystals in the mineralized bone matrix, resisting degradation and preserving the bone structure. Moreover, bones can serve as reservoirs for toxic metals, which may be released slowly into the bloodstream, leading to various adverse effects.