ABSTRACT
Large interindividual differences in drug response to psychotropic drugs is more of a rule than an exception. In fact, among patients treated with the same dose, psychotropic drug response varies widely from no effect at all to severe adverse drug reactions. Many factors contribute to this variability and, apart from the role of non-pharmacological aspects, such as psycho logical and social implications, it mainly results from the interaction of genetic, pathophysiological and environmental factors that lead to inter individual differences in drug pharmacokinetics and pharmacodynamics. Kinetic processess such as passive diffusion are rate-limited by the physicochemical characteristics of the drug, therefore they are not likely to vary significantly among patients unless pathophysiological factors exert an influence. In contrast, although not all the variations in psychotropic drug response involve drug metabolism, pharmacogenetic research has since the 1970s, and the discovery of the debrisoquine/sparteine hydroxylation polymorphism, expanded vigorously in the study of the interplay between environmental and genetic factors controlling the rate of drug metabolism and, hence, drug response (Sjoqvist et a l., 1997). Currently it is well known that the CYP-mediated reactions typically show pronounced interindividual variability, leading to large differences in steady-state plasma concentrations of drugs and, therefore, in therapeutic outcome. The vari ability in drug metabolism is mainly due to genetic factors which regulate the activity of CYPs. Additionally, they may be influenced by a number of factors such as concomitant drug administration, diet (coffee, alcohol, grapefruit juice, cruciferous vegetables, charcoal broiling meat), occupa tional exposure to environmental pollutants and smoking, among others. With a few exceptions, psychotropic drugs are lipophilic agents that under go extensive metabolism in the liver, yielding polar metabolites that can be easily excreted in the urine (Caccia and Garattini, 1990). In general, their metabolism involves phase I oxidative reactions, catalysed by cytochrome P450 enzymes (CYPs), followed by phase II glucuronide conjugation.
