Hydrophobicity and Central Nervous System Agents: On the Principle of Minimal Hydrophobicity in Drug Design

The problem of getting drugs across the so-called blood-brain bárrier (BBB) has long been under extensive investigation; however, the other side of the problem, that of keeping drugs out of the central nervous system (CNS), has not been studied so intently. As we strive to make more and more refined drugs with fewer side effects, the problem of keeping drugs out of the CNS has possibly become more important than getting them in. The role of lipophilicity has long been recognized as being important in CNS penetration by chemicals, but we believe that not enough attention has been devoted to just exactly what is meant when it is said that “a lipophilic drug is needed for CNS penetration.” How lipophilic? Can hydrophilic properties keep drugs out of the CNS? How hydrophilic should they be? There are other reasons for making drugs hydrophilic. Hydrophobic drugs, other factors being equal, are more inhibitory of biochemical systems than hydrophilic congeners. Evidence is beginning to show that cytochrome P450 is induced in direct proportion to hydrophobicity by a variety of compounds, and cytochrome P450 may produce modifications in lipophilic molecules in the body. Hydrophobic drugs are more slowly eliminated. This report discusses these problems in terms of the octanol-water (log P) hydrophobic scale. The principle is proposed that, without convincing evidence to the contrary, drugs should be made as hydrophilic as possible without loss of efficacy. Antihistamines are discussed in terms of what kind of hydrophobic-hydrophilic balance is best to avoid CNS-related problems.