Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms

Spigset, Olav; Granberg, Kerstin; Hägg, Staffan; Norström, Åke; Dahlqvist, Rune

doi:10.1007/s002280050261

Cited by 69 publications

(55 citation statements)

References 18 publications

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“…Because desipramine is mainly metabolized by a single enzyme, CYP2D6, it been used widely as a probe drug for CYP2D6 activity (Ball et al, 1997;Kurtz et al, 1997;Spigset et al, 1997;Spina et al, 1997;Madani et al, 2002). High ratios of desipramine to parent drug due to impaired metabolism caused by the CYP2D6 PM phenotype have been related to increased frequency of adverse drug reactions, and even death, upon chronic administration of therapeutic doses (Swanson et al, 1997;Leucht et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

Nguyen

Callegari

Obach

2016

Drug Metabolism and Disposition

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Major circulating drug metabolites can be as important as the drugs themselves in efficacy and safety, so establishing methods whereby exposure to major metabolites following administration of parent drug can be predicted is important. In this study, imipramine, a tricyclic antidepressant, and its major metabolite desipramine were selected as a model system to develop metabolite prediction methods. Imipramine undergoes N-demethylation to form the active metabolite desipramine, and both imipramine and desipramine are converted to hydroxylated metabolites by the polymorphic enzyme CYP2D6. The objective of the present study is to determine whether the human pharmacokinetics of desipramine following dosing of imipramine can be predicted using static and dynamic physiologically-based pharmacokinetic (PBPK) models from in vitro input data for CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) populations. The intrinsic metabolic clearances of parent drug and metabolite were estimated using human liver microsomes (CYP2D6 PM and EM) and hepatocytes. Passive diffusion clearance of desipramine, used in the estimation of availability of the metabolite, was predicted from passive permeability and hepatocyte surface area. The predicted area under the curve (AUC m /AUC p ) of desipramine/imipramine was 12-to 20-fold higher in PM compared with EM subjects following i.v. or oral doses of imipramine using the static model. Moreover, the PBPK model was able to recover simultaneously plasma profiles of imipramine and desipramine in populations with different phenotypes of CYP2D6. This example suggested that mechanistic PBPK modeling combined with information obtained from in vitro studies can provide quantitative solutions to predict in vivo pharmacokinetics of drugs and major metabolites in a target human population.

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Section: Discussionmentioning

confidence: 99%

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

Nguyen

Callegari

Obach

2016

Drug Metabolism and Disposition

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“…Therefore, multiple dosing causes auto-inhibition of CYP2D6 and conversion from extensive to slow metabolizer phenotype and from ultrafast to extensive metabolism was described. 13,14 In the case of fluvoxamine, differences in concentration-time curves (AUCs) between CYP2D6 genotypes were described after single doses, 15,16 whereas multiple doses result in similar AUCs in PMs and in EMs indicating a strong inhibitory effect on CYP2D6 in EMs. 17 For fluoxetine undergoing enantioselective metabolism toward the S-enantiomer, impaired demethylation of Sfluoxetine in CYP2D6 PMs was observed.…”

Section: Tricyclic Antidepressantsmentioning

confidence: 99%

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

et al. 2007

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“…The K e was approximately 1.3-fold higher in mice injected at 9:00 PM than at 9:00 AM. The major metabolic pathway of fluvoxamine is oxidative demethylation and oxidative deamination in the liver (Overmars et al, 1983), and fluvoxamine is metabolized by CYP1A2 and CYP2D6 in human (Carrillo et al, 1996;Spigset et al, 1997). The expression of CYP1A2 mRNA is observed in mice (Dey et al, 1999), but 24-h rhythms of mRNA expression and enzyme activity of mouse CYP1A2 have not been clarified yet.…”

Section: Influence Of Dosing Time On Anti-immobilizing Effect 767mentioning

confidence: 99%

Chronopharmacological Study of Antidepressants in Forced Swimming Test of Mice

Ushijima

Sakaguchi

Sato

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

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The influence of dosing time on the anti-immobility effect of antidepressants and mechanisms underlying this phenomenon were investigated in mice. In the forced swimming test (FST), the immobility time of mice treated with amitriptyline (15 mg/kg) and fluvoxamine (30 mg/kg) showed a significant 24-h rhythm. The anti-immobility effect of fluvoxamine in FST was potent at the early part of the dark phase without increasing locomotor activity. Concerning pharmacokinetics, although K e of fluvoxamine was approximately 1.3-fold higher in mice injected with fluvoxamine at 9:00 PM than at 9:00 AM, no dosing time dependence was demonstrated for either plasma or brain fluvoxamine concentration at 0.5 h after the drug injection. On the other hand, serotonin transporter (SERT) mRNA expression and 5-hydroxytryptamine (5-HT) uptake activity in the mouse midbrain showed significant time-dependent changes with higher levels during the dark phase and lower levels during the light phase. These results suggest that the reuptake of 5-HT might be more increased during the dark phase. Since the reuptake of 5-HT is inhibited almost completely by injection with 30 mg/kg fluvoxamine at any time, the extracellular 5-HT level may be more increased by the injection of fluvoxamine at the early part of the dark phase. The present results suggest that the antiimmobility effect of fluvoxamine in FST increases depending on dosing time. Furthermore, the time-dependent change of SERT mRNA expression and uptake activity in the midbrain is suggested to be the mechanism underlying the 24-h rhythm of anti-immobility effect of fluvoxamine.

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Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms

Abstract: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism.

Cited by 69 publications

References 18 publications

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

Chronopharmacological Study of Antidepressants in Forced Swimming Test of Mice

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