Lack of Pharmacokinetic Interaction between Antipsychotics (Quetiapine, Clozapine and Olanzapine) and the Beta-Blockers Metoprolol, Propranolol, Bisoprolol and Nebivolol Except between Carvedilol and the Antipsychotics Quetiapine and Clozapine

Abstract

The purpose of this study was to evaluate a potential pharmacokinetic interaction between antipsychotics (quetiapine QUE, clozapine CLO and olanzapine OLA) and beta-blockers (metoprolol MET, propranolol PRO, bisoprolol BIS, nebivolol NEB and carvedilol CAR). Antipsychotics and beta-blockers are metabolized by the same cytochrome-P450 (CYP)-isoenzymes, which are inhibited by representatives of both substance classes. Pooled human liver microsomes (HLM) and recombinant CYP isoenzymes were used to determine whether the investigated antipsychotics and beta-blockers inhibit the metabolism of each other. Drug concentrations have been measured by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Experiments with HLM showed that the metabolism of QUE as well as CLO slowed down in presence of CAR. There was no significant difference between the metabolism of the antipsychotics alone and the metabolism in combination with BIS, NEB and the two known CYP2D6-inhibitors MET and PRO. Experiments with recombinant CYP2D6 demonstrated an inhibitory effect on the metabolism of QUE and CLO by MET, PRO, NEB and CAR. The results suggest that CAR is also an inhibitor of other CYP enzymes, which are involved in the metabolism of CLO and QUE. It is assumed that CYP2D6 is a minor pathway of the antipsychotics and that the CYP2D6-inhibitory-effect of MET, PRO and NEB is compensated through a higher metabolism rate via the metabolic pathways of the other CYP-isoforms.