WHAT IS KNOWN AND OBJECTIVE: Paroxetine is both a substrate and an inhibitor of CYP2D6. The objective of the presented study was to determine the persistence of CYP2D6 inhibition after short term (6 weeks) and long term (18·7 ± 10·6 weeks) paroxetine treatment. METHODS: Two the studies consisted of 30 depressive/anxiety patients each. In the first study, patients were subdivided into three groups treated with paroxetine (A1), alprazolam (A2) and paroxetine + alprazolam (A3). After 6 weeks, all the patients (A1+A2+A3) were switched to alprazolam treatment; metabolic activity was evaluated at the beginning, after 6 weeks of paroxetine/alprazolam/alprazolam + paroxetine treatment (A1/A2/A3) and 4 weeks after the switch to alprazolam treatment (Week 0, 6, 10). In the second study patients on previous long term paroxetine treatment were subdivided into two groups treated with mirtazapine (B1) or paroxetine (B2); metabolic activity of CYP2D6 was evaluated at the beginning and after 6 weeks of therapy. RESULTS AND DISCUSSION: Metabolic ratio of dextromethorphan to dextrorphan has normalized in all subjects after 4 weeks of paroxetine wash out in the first study. In the second study, 6 weeks after paroxetine discontinuation, restoration of metabolic activity of CYP2D6 was observed in only five of eight originally poor metabolizers. WHAT IS NEW AND CONCLUSION: We conclude that a wash-out period of 4 weeks seems to be sufficient for CYP2D6 disinhibition after short-term paroxetine treatment (6 weeks). On the other hand, treatment with a CYP2D6 substrate less than 6 weeks after long-term paroxetine treatment (18·7 weeks on average) could result in elevated drug plasma levels and occasionally also in drug toxicity.

• MeSH
• alprazolam farmakologie   MeSH
• cytochrom P-450 CYP2D6 metabolismus   MeSH
• deprese farmakoterapie   enzymologie   metabolismus   MeSH
• dextromethorfan farmakologie   MeSH
• dextrorfan farmakologie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• inhibitory cytochromu P450 CYP2D6 MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• paroxetin farmakologie   MeSH
• senioři MeSH
• úzkost farmakoterapie   enzymologie   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

WHAT IS KNOWN AND OBJECTIVE: Accurate prediction of actual CYP2D6 metabolic activity may prevent some adverse drug reactions and improve therapeutic response in patients receiving CYP2D6 substrates. Dextromethorphan-to-dextrorphan metabolic ratio (MR(DEM/DOR)) is well established as a marker of CYP2D6 metabolizer status. The relationship between urine and plasma or serum MR(DEM/DOR) is not well established nor is there evidence of antimode for separation of intermediate and especially poor metabolizers (PM) from extensive metabolizers (EM). This study addressed whether CYP2D6 phenotyping using molar metabolic ratio of dextromethorphan to dextrorphan (MR(DEM/DOR)) in serum is usable and reliable in clinical practice as urinary MR(DEM/DOR). METHODS: We measured MR(DEM/DOR) in serum and CYP2D6 genotype in 51 drug-naive patients and 30 volunteers. Receiver-operator characteristic (ROC) analysis was used for the evaluation of optimum cut-off value for discriminating between extensive, intermediate and PM. In addition, we studied the correlation of serum MR(DEM/DOR) with urine MR(DEM/DOR) in the 30 healthy volunteers. RESULTS AND DISCUSSION: A trimodal distribution of log MR(DEM/DOR) in serum was observed, with substantial overlap between extensive and intermediate metabolizer groups. We obtained an acceptable cut-off serum MR(DEM/DOR) value to discriminate between PM and either extensive or extensive + intermediate metabolizers. Using serum MR(DEM/DOR), it seems to be unreliable to discriminate EM from intermediate metabolizers (IM). A strong correlation between serum MR(DEM/DOR) and urine MR(DEM/DOR) was found. WHAT IS NEW AND CONCLUSION: Serum MR(DEM/DOR) (3 h) correlated with MR(DEM/DOR) in urine (0-8 h). Serum MR(DEM/DOR) discriminated between extensive and PM and between extensive + intermediate and PM. Our CYP2D6 phenotyping using serum dextromethorphan/dextrorphan molar ratio appears reliable but requires independent validation.

• MeSH
• cytochrom P-450 CYP2D6 genetika   MeSH
• dextromethorfan aplikace a dávkování   farmakokinetika   MeSH
• dextrorfan farmakokinetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• genotyp MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• ROC křivka MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH

OBJECTIVES: Differences in the metabolism between males and females have been seen over time. Hormonal regulation of cytochrome P450 activity is understood to be involved. Trans-resveratrol (RES) is an estrogenically active plant polyphenol with many protective biological activities including neuroprotection. The present report studied the influence of sex and RES on variances in rat's cytochrome P450 2D2 hepatic metabolic activity. METHODS AND DESIGN: Isolated perfused rat liver was used for determination of cytochrome P450 2D2 activity. Wistar albino rats of both sexes were treated with RES at the dose of 5 mg/kg/day for 10 days prior to liver isolation. Levels of marker substance dextromethorphan (DEM) and its 2D2 specific metabolite dextrorphan (DEX) were measured during perfusion. The metabolic ratios (DEM/DEX) and the levels of DEM and DEX in perfusate were compared. RESULTS: In the controls, the activity of CYP2D2 was found to be higher in male rats compared to females. RES produced inhibition of CYP2D2, expressed by significant changes of both DEM and DEX levels in males and significant increase of only DEM levels in females. There were no gender changes in DEX levels in RES treated animals whilst DEM levels were significantly increased during the whole perfusion in females. CONCLUSION: The results confirmed gender differences in the metabolic activity of CYP450 2D2 with a higher rate in male rats. RES acted as an inhibitor, however again with greater impact in males than in females. This metabolic divergence could be a cause for different sensitivity or even toxicity of drugs metabolized by the CYP450 2D2.

• MeSH
• aromatické hydroxylasy antagonisté a inhibitory   metabolismus   MeSH
• dextromethorfan chemie   metabolismus   MeSH
• dextrorfan chemie   metabolismus   MeSH
• inhibitory cytochromu P450 MeSH
• inhibitory enzymů farmakologie   MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• pohlavní dimorfismus MeSH
• potkani Wistar MeSH
• stilbeny farmakologie   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• PARALEN PLUS,
• MeSH
• dextrorfan farmakokinetika   MeSH
• léky bez předpisu MeSH
• lidé MeSH
• paracetamol farmakokinetika   MeSH
• Check Tag
• lidé MeSH

Projek se zabývá vztahy mezi imunologickými faktory a metabolismem léčiv. Na preklinické a molekulární úrovni budou studovány mechanismy změn vyvolaných imunostimulátory a imunosupresivy v oxidativním a acetilačním metabolismu.

• MeSH
• acetylprokainamid analýza   MeSH
• dextromethorfan analýza   MeSH
• dextrorfan analýza   MeSH
• interpretace statistických dat MeSH
• prokainamid analýza   MeSH
• věda o laboratorních zvířatech MeSH
• vysokoúčinná kapalinová chromatografie využití   metody   MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• farmacie a farmakologie
• alergologie a imunologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

• MeSH
• dexamethason aplikace a dávkování   farmakologie   MeSH
• dextromethorfan aplikace a dávkování   metabolismus   MeSH
• dextrorfan aplikace a dávkování   metabolismus   MeSH
• imunosupresiva aplikace a dávkování   farmakologie   MeSH
• játra metabolismus   účinky léků   MeSH
• krysa rodu rattus MeSH
• systém (enzymů) cytochromů P-450 aplikace a dávkování   metabolismus   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• dextromethorfan analýza   metabolismus   moč   MeSH
• dextrorfan analýza   metabolismus   moč   MeSH
• imunofenotypizace metody   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH

• MeSH
• dextrorfan farmakologie   MeSH
• kokain MeSH
• krysa rodu rattus MeSH
• mozkový kmen patofyziologie   účinky léků   MeSH
• pohybová aktivita účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH