Pharmacokinetic determinants of drug abuse and dependence. A conceptual perspective

Drugs that produce physical dependence or have similar pharmacological profiles to highly abused drugs are unlikely to be considered acceptable for marketing. Thus, the prediction of abuse and dependence becomes an important issue in the development of new psychotropic drugs. Both pharmacokinetic and non-pharmacokinetic factors play an important role in predicting dependence and abuse liability of drugs. Evidence for the importance of pharmacological factors includes: the demonstration of drug binding to receptors of abused drugs; tolerance; ability to maintain self-administration; and spontaneous or antagonist precipitated withdrawal. The pharmacokinetic properties that presumably contribute to persistent self-administration and abuse include rapid delivery of drug to the central nervous system (CNS), rapid absorption, low protein binding and high free drug clearance. The pharmacokinetic properties of a drug associated with dependence will include long half-life, low free drug clearance and presence of the drug in the body at high enough concentrations and for sufficient time to permit tolerance to develop. These properties have important clinical implications for treatment and research in the area of abuse and dependence liability of psychoactive drugs.