The Role of Cytochrome P450 Enzymes in the Metabolism of Risperidone and Its Clinical Relevance for Drug Interactions

Abstract

In the recent years it has been increasingly recognized that pharmacogenetical factors play an important role in the drug treatment. These factors may influence the appearance of side-effects and drug interactions due to interindividual differences in the activity of metabolizing enzymes. Risperidone in humans is mainly metabolized to 9-hydroxyrisperidone by the polymorphic cytochrome enzyme P450 2D6 (CYP2D6). Plasma concentrations of risperidone and 9-hydroxyrisperidone show large interindividual variability, which may be partly related to the activity of the CYP2D6 enzyme. Around seven percent of Caucasians have a genetically inherited impaired activity of the CYP2D6 enzyme. Debrisoquine metabolic ratio (a marker of CYP2D6 activity) and the number of CYP2D6 active genes have been related to risperidone plasma concentrations among patients during steady-state conditions. A large number drugs have been described to be metabolized by CYP2D6, and it is therefore important to evaluate the clinical significance of the impaired metabolism and possible drug interactions on the enzyme. Since risperidone/9-hydroxyrisperidone ratio strongly correlates with CYP2D6 enzyme activity and the number of CYP2D6 active genes, thus it might be a useful tool in clinical practice to estimate the possible risk of drug interactions due to impaired CYP2D6 enzyme activity. CYP3A4 is the most abundant drug metabolizing enzyme in humans, and in vitro and in vivo results suggest also a role for the enzyme in risperidone metabolism. The consideration of the implication of cytochrome P450 enzymes in risperidone metabolism may help to individualize dose schemes in order to avoid interactions and potentially dangerous side-effects, such us QTc interval lengthening among patients with cardiac risk factors.

Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents

“…In accord with this finding CYP2D6 PM subjects had an increased ratio of risperidone to 9-hydroxyrisperidone but no overall difference in the concentration of the active moiety (Olesen et al 1998). However, possibly as a result of the pharmacological activity of 9-hydroxyrisperidone, the significance of the CYP2D6 phenotype for the safety and efficacy of the drug remains unclear (Scordo et al 1999;Berecz et al 2004).…”

“…The debrisoquine metabolic ratio (an in-vivo marker of CYP2D6 activity) and the number of active CYP2D6 genes have been related to steady-state plasma concentrations of risperidone in patients (Berecz et al 2004). Recently, a large study of 136 schizophrenic patients who received risperidone was concluded (Kakihara et al 2005).…”

Acute Toxic Hepatitis Due To Risperidone Use: Case Report

“…Bireyler arası dozlardaki farklılıklar ilaç yan etkisiyle ilişkili olabilir. Ek olarak CYP2D6 genetik polimorfizmi ve plazma risperidon ve hidroksirisperidon düzeylerinin değerlendirilmesi yan etki potansiyelini azaltabilir 5,12 . Risperidonun kesilmesiyle vakanın mevcut şikayetlerini yatıştırmaya yönelik parenteral haloperidol tedavisi ve lorazepam tedavisi başlandı.…”

Unwanted Interactions Among Psychotropic Drugs and Other Treatments for Autism Spectrum Disorders

“…45 Risperidone is metabolized and can contribute to numerous drug interactions because it is metabolized by CYP3A4, the most common drug-metabolizing enzyme. 46 Many children have GI problems 47 and are given numerous medications that change the GI flora. In particular, they are often given antifungal medications, 16,17 such as fluconazole, which is a CYP3A inhibitor and can affect the metabolism of many drugs (Fig.…”