Low daily 10‐mg and 20‐mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19)

Christensen, Magnus; Tybring, Gunnel; Mihara, Kazuo; Yasui‐Furokori, Norio; Carrillo, Juan Antonio; Ramos, Sara I.; Andersson, Kjell; Dahl, Marja­‐Liisa; Bertilsson, Leif

doi:10.1067/mcp.2002.121788

Cited by 79 publications

(55 citation statements)

References 45 publications

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“…This was in line with previous interaction studies indicating that dose or plasma concentration of fluvoxamine correlated well with the degree of inhibition in the metabolism of various drugs such as clozapine (Markowitz et al 1996;Fabrazzo et al 2000), melatonin (von Bahr et al 2000) and omeprazole (Christensen et al 2002). In addition, we found positive correlations between increase in haloperidol concentra- Drug concentrations (ng/ml) Haloperidol 3.7€4.4 (1.9-6.9) 4.4€1.7 (2.4-7.9)*** 5.2€2.3 (2.5-10.0)** 6.0€3.0 (2.7-12.6)** Reduced haloperidol 1.5€1.7 (0.5-3.1) 1.7€0.9 (0.6-3.8)* 1.9€1.1 (0.8-4.5)* 2.3€1.2 (0.9-4.6)** Fluvoxamine -16.9€9.8 (4.5-37.5) 55.…”

Section: Discussionsupporting

confidence: 88%

“…In addition, we found positive correlations between increase in haloperidol concentra- Drug concentrations (ng/ml) Haloperidol 3.7€4.4 (1.9-6.9) 4.4€1.7 (2.4-7.9)*** 5.2€2.3 (2.5-10.0)** 6.0€3.0 (2.7-12.6)** Reduced haloperidol 1.5€1.7 (0.5-3.1) 1.7€0.9 (0.6-3.8)* 1.9€1.1 (0.8-4.5)* 2.3€1.2 (0.9-4.6)** Fluvoxamine -16.9€9.8 (4.5-37.5) 55. 2€27.8 (15.4-110) 139 Fluvoxamine is known as not only a potent inhibitor of CYP1A2 and CYP2C19 (Christensen et al 2002), but also a moderate inhibitor of CYP3A4, based on in vivo (Fleishaker et al 1994) and in vitro (von Moltke et al 1995) interaction studies between fluvoxamine and alprazolam, which is a specific substrate of CYP3A4 (Yasui et al 1996). In a previous study, we found that itraconazole, a potent inhibitor of CYP3A4, elevated haloperidol concentration, indicating the involvement of CYP3A4 in the metabolism of haloperidol (Yasui et al 1999).…”

Section: Discussionmentioning

confidence: 99%

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Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

et al. 2004

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Augmentation with low-dose fluvoxamine (50-100 mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6 mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150 mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150 mg/day were 120% (95%CI; 114-127%), 139% (95%CI; 130-149%), and 160% (95%CI; 142-178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

et al. 2004

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“…Fluvoxamine is metabolized in part by CYP2D6 and to a lesser extent by CYP1A2 ). Data are PHARMACOGENETICS, DRUG METABOLISM, AND CLINICAL PRACTICE conflicting regarding the effect of CYP2D6 on fluvoxamine concentrations, with a single-dose study reporting a 1.3-fold higher AUC in PMs , whereas in another no difference was observed (Christensen et al, 2002). Similar disparities were observed at steady state (Spigset et al, 1998;Christensen et al, 2002).…”

Section: Doxepin (Tertiary)/desmethyldoxepin (Secondary)mentioning

confidence: 51%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…[36][37][38] Enzyme inhibition by the substrate itself was described to convert genotypic extensive metabolizers of CYP2D6 substrates to phenotypically poor metabolizers in antidepressant drug therapy. [39][40][41] Drug target polymorphisms Data analysis We included all available studies concerning response to therapy and adverse drug reactions. We did not include studies on genetic polymorphisms as risk factors for the genetic susceptibility to mental illness.…”

Section: Metabolic Polymorphismsmentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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Low daily 10‐mg and 20‐mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19)

Cited by 79 publications

References 45 publications

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

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