THAM is a titrating agent in vivo as well as in vitro, and its ionized fraction acts in the kidney as a non-reabsorbable cation. Since, at normal blood pH, THAM is 70% ionized, the larger part of the compound remains in the extracellular fluid and is rapidly excreted in the presence of a functional kidney. By reducing the pCO2 in the extracellular space, THAM could reduce intracellular pH as well. However, such a reduction of intracellular pCO2 is limited by TIJAM's depressant effect on ventilation, an effect which rapidly restores to normal and then elevates plasma pCO2 in the presence of an alkaline pH. The fraction of THAM which penetrates into the cells is, at intracellular pH, 90% ionized and may "overtitrate" the intracellular spaces. As ionized THAM accumulates in the cell, K+ moves out in order to restore the normal Donnan ratio. In addition to this action on by migration, THAM does not act as a simple buffer inside the cell but most likely interacts with enzyme systems. These interactions remain to be determined and distinguished from the pH effect of THAM. Compounds similar to THAM which would penetrate at a relatively slow rate into cells and modify intracellular pH would be very useful (90) in experimental work in order to alter the activity of specific enzymes. However, their ready availability is unlikely, primarily because of the instability of most organic compounds in vivo. Meanwhile, THAM is a very useful tool for the physiologists and pharmacologists who wish to study the effects of acid-base balance alterations. When used judiciously it has also been helpful in clinical medicine. During acidosis, severe metabolic disturbances overwhelm homeostatic mechanisms and many forms of therapy become ineffective. The administration of THAM, by restoring pH of body fluids to normal, potentially can provide optimum conditions for the restoration of homeostasis and for standard therapeutic procedures.