Physicochemical considerations and pharmacokinetic behavior in delivery of drugs to the central nervous system.

The blood-brain barrier is not as rigid or as formidable as once believed. When experimental tumors of the central nervous system (CNS) and tumors of non-CNS origin are implanted intracerebrally (ic), they will grow and kill the host. It was once thought that only a few select agents, such as the nitrosoureas, were capable of crossing the blood-brain barrier and inhibiting tumor growth. There are now considerable data available which indicate that a variety of agents such as cytosine arabinoside, methotrexate, 6-mercaptopurine, 5-fluorouracil, procarbazine, melphalan, and cyclophosphamide, as well as the nitrosoureas, may significantly influence the growth rate of experimentally implanted ic tumors. A number of physicochemical factors may influence the penetration of the blood-brain barrier. These include pKa values, log-P values, and molecular size. Brain-level measurements indicate that most drugs have some accessibility to the CNS. Maximal effects against sensitive, ic implanted tumors are attained through maximal scheduling. Effective drug combinations should be sought to further enhance antitumor effects in the CNS.