fluvoxamine and Ataxia

A patient had phenytoin intoxication after administration of fluvoxamine, a selective serotonin reuptake inhibitor. The serum concentration of phenytoin increased dramatically from 16.6 to 49.1 microg/mL when fluvoxamine was coadministered, although the daily dosage of phenytoin and other drugs had not changed. During phenytoin and fluvoxamine treatment, ataxia, a typical side effect of phenytoin, was observed. The genotypes of CYP2C9 and 2C19, the enzymes responsible for phenytoin metabolism, were homozygous for the wild-type alleles (CYP2C9*1/*1 and 2C19*1/ *1). The interaction may be a result of inhibition of both CYP2C9 and 2C19 by fluvoxamine.

Topics: Alleles; Anticonvulsants; Antidepressive Agents, Second-Generation; Aryl Hydrocarbon Hydroxylases; Ataxia; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Fluvoxamine; Genotype; Humans; Middle Aged; Mixed Function Oxygenases; Phenytoin; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases

Fluvoxamine, a selective serotonin reuptake inhibitor, is frequently used along with benzodiazepine anxiolytics in clinics. In this study, the effects of fluvoxamine on the anxiolytic effects as well as adverse effects of benzodiazepines were examined in the light/dark box, rota-rod and passive avoidance tests using mice. Diazepam, ethyl loflazepate and its active metabolite, CM7116, were used as benzodiazepine anxiolytics. The anxiolytic effects of diazepam, ethyl loflazepate and CM7116 were potentiated by intraperitoneal treatment with fluvoxamine at 10 mg/kg, whereas only those of ethyl loflazepate were potentiated by fluvoxamine at 45 mg/kg. The motor incoordination and amnesia induced by ethyl loflazepate and CM7116 were not affected by fluvoxamine, although these adverse effects of diazepam were potentiated by fluvoxamine at 45 mg/kg. Fluvoxamine itself showed no effects in any of the tests. These results suggest that low-dose fluvoxamine potentiates the anxiolytic effects of benzodiazepines, while high-dose fluvoxamine augments the adverse effects depending on the benzodiazepine used. Consequently, when fluvoxamine is administered along with benzodiazepines, the doses of both fluvoxamine and benzodiazepines should be carefully chosen to achieve anxiolytic effects without any adverse results.

Topics: Amnesia; Animals; Anti-Anxiety Agents; Ataxia; Benzodiazepines; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Fluvoxamine; Male; Mice; Mice, Inbred Strains; Selective Serotonin Reuptake Inhibitors