Antifolates: in vivo kinetic considerations.

The action of antimetabolites in vivo involves the consideration of several interrelated factors. If the mechanism of biochemical action is understood, the next items of priority are whether the active form of the drug gets to the site of action, its concentration at this site, the time course of removal of active drug from this site, and how these kinetics relate to the biochemical inhibition. Studies of antifolates represent some of the approaches used to further understand antimetabolite action in vivo. The interrelationships of blood flow, mixing volumes of tissue compartments, membrane resistance, binding of drug, binding site formation, transport competition, and biochemical kinetics of rate-limiting steps, substrate competition, and salvage pathways are considered from an in vivo point of view.