Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers

Skinner, Michael H.; Kuan, Han-Yi; Pan, Alan X.; Sathirakul, Korbtham; Knadler, Mary Pat; Gonzales, Celedon; Yeo, Kwee Poo; Reddy, Shobha; Lim, Mervyn Jun Rui; Ayan-Oshodi, Mosun; Wise, Stephen D.

doi:10.1067/mcp.2003.28

Cited by 165 publications

(121 citation statements)

References 12 publications

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“…9 The new atypical antidepressant duloxetine is a potent inhibitor of CYP2D6 in vivo and a CYP2D6 substrate in vivo. 43 It therefore seems probable that CYP2D6 genetic polymorphisms have a major impact on elimination of this drug, but this has not yet been studied in detail.…”

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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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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“…While assessment of possible pharmacokinetic interactions is required whenever prescribing multiple medications in HIV illness, the complexity and number of potential medication combinations make it impractical for any clinician to memorize all potential interactions. Therefore, a general understanding of the underlying kinetic principles can greatly assist in identifying potential interactions, with the help of references such as Table 4 [71][72][73][74][75] and the Physicians' Desk Reference. 76 Oxidative enzymes responsible for the metabolism of drugs are divided into families and subfamilies named according to the cytochrome P450 variants (1A2, 2D6, 3A4, etc.).…”

Section: Selecting and Using Antidepressantsmentioning

confidence: 99%

Human Immunodeficiency Virus and Depression in Primary Care

Colibazzi

Hsu

Gilmer

2006

Prim. Care Companion CNS Disord.

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“…Weaker duloxetine concentration increases may also be observed with CYP 2D6 inhibitors such as paroxetine. 24 Duloxetine does not appear to have a significant effect on the metabolism of drugs that are substrates of CYP1A2 such as theophylline. 25 In smokers, significantly lower concentrations of duloxetine serum levels than those expected in the general population, are found.…”

Section: Mechanism Of Action Metabolism and Pharmacokinetic Profilementioning

confidence: 99%

“…19,20 What is known about metabolism and pharmacokinetics? 17,23,24 Duloxetine is well absorbed (extent 70%) when orally administered (mean oral bioavailibity of 50%). The time to peak concentration is approximately 6 hours in fasted subjects, with the available form of duloxetine which consists of capsules containing enteric-coated pellets.…”

Section: Mechanism Of Action Metabolism and Pharmacokinetic Profilementioning

confidence: 99%

Pharmacotherapy of Fibromyalgia: Focus on Duloxetine

Serra

Andréjak

2009

Clinical Medicine. Therapeutics

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Context: Fibromyalgia syndrome (FMS) is a frequent medical condition characterized by chronic widespread pain and reduced pain threshold. Associated symptoms include fatigue, non restorative sleep, and psychological distress. As usual in medicine, even if the pathogenesis is unclear, some treatments are useful to help patients. Objectives: Tricyclic antidepressants were the first drugs used to treat FMS. More recently, among serotonin-norepinephrine reuptake inhibitors, duloxetine was approved by US Food and Drug Administration to treat FMS. Duloxetine is used for the management of major depressive disorder, neuropathic pain, generalized anxiety disorder, and stress incontinence. In the pharmacotherapy of fibromyalgia, a focus is presented on the drug duloxetine. Results: Mechanism of action, metabolism and pharmacokinetic profile are presented. Clinical studies of Duloxetine showed an acceptable efficacy for this chronic condition: Number Need to Treat (NTT) of 4.7 to 9.9, through two 3-month placebo-controlled trials and two 6-month trials. Evaluation criteria are discussed. Safety of this medication has been found to be satisfactory, with nausea as the most common adverse event, in almost 20% of cases. Conclusion: Treatment algorithm for duloxetine is presented inside FMS treatment strategy. With duloxetine, it is important to start low and increase slowly to prevent or minimize adverse events: 30 mg/day up to 60 mg/day in the second week and if necessary up to 90-120 mg/day. It is possible to treat for 3 to 6 months, possibly up to 12 months. The drug could be decreased 2 to 4 weeks before stopping, with regular assessments during this time. International recommendations insist on multimodal treatments: drug and non drug. Also effective for anxiety and depression, duloxetine ranks among the first place drugs for FMS.

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Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers

Cited by 165 publications

References 12 publications

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

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

Human Immunodeficiency Virus and Depression in Primary Care

Pharmacotherapy of Fibromyalgia: Focus on Duloxetine

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