Pharmacokinetics: selectivity of action related to physicochemical properties and kinetic patterns of anticancer drugs.

Since the therapeutic index of drugs used for the treatment of cancer is small, optimal use depends on whatever advantage can be gained by achieving an effective concentration at the critical site in the cancer cell for a period of time sufficient to kill that cell while minimizing the action on normal cells or allowing their recovery. Advances in 1) methodology for measurement of minute amounts of drugs in tissues and body fluids, 2) better understanding of cell cycle kinetics and 3) development of kinetic models and computer simulation of compartmental drug distribution now aid better choice of dosage, mode of administration and treatment schedules. Limitations on the entry of amethopterin (Methotrexate) into cells and body compartments is compared with another folate antagonist, metroprine (DDMP), having the same mode of action, yet able to penetrate into brain. CSF and amethopterin-resistant cells because of greater lipid solubility. Pharmacokinetic considerations related to the limited effectiveness of present drugs for the treatment of brain tumors lead to the concept of "compartmental chemotherapy" based on selective drug contact with tumor combined with selective protection of tissues of limiting toxicity.