Systemic and presystemic conversion of carbamazepine to carbamazepine-10,11-epoxide during long term treatment

Fagiolino, Pietro; Vázquez, Marta; Olano, Ivette; Delfino, Aurora

doi:10.1590/s1676-26492006000100004

Cited by 14 publications

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“…Then CBZ concentration in saliva is non-linearly related with daily dose as it was previously reported for plasma CBZ concentrations. 1 This non-linear pharmacokinetic response is explained by its autoinductive effect, the higher the administered dose is, the higher the clearance becomes.…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid

Maldonado¹,

Fagiolino²,

Vázquez³

et al. 2008

J. epilepsy clin. neurophysiol.

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Objective: The aim of the study was to analyze retrospectively carbamazepine (CBZ) and valproic acid (VPA) salivary data collected from epileptic children during a 3-year period. Methods: Saliva samples stimulated by citric acid were assayed by FPIA method. One hundred and three patients (aged 1-14 years) were in CBZ or VPA monotherapy or in CBZ-VPA combined therapy. Results: VPA salivary levels were linearly related with daily dose, but a non-linear relationship was found for CBZ, in patients under monotherapy. VPA did not alter saliva CBZ concentration. Conversely, CBZ reduced VPA salivary levels. Non-responsive children displayed higher VPA concentrations. CBZ levels in uncontrolled patients showed non-significant difference in relation with controlled subjects even though their daily doses were higher. Conclusion: Citric acid stimulated saliva is reliable enough to perform therapeutic drug monitoring. Saliva drug levels in non-responsive patients would be explained according to the generalized efflux transporter overexpression hypothesis.Keywords: Saliva concentration, carbamazepine, valproic acid, refractory epilepsy, efflux transporters. RESUMO Monitoramento terapêutico de carbamazepina e ácido valproico em saliva de criançasObjetivo: O objetivo deste estudo foi avaliar retrospectivamente por 3 anos a partir de dados salivares, as terapias com carbamacepina (CBZ) e ácido valproico (VPA) em pacientes pediátricos. Métodos: Foram avaliadas amostras de saliva estimuladas com ácido cítrico por método FPIA em 103 pacientes (idades 1-14 anos) em monoterapia com CBZ ou VPA ou terapia combinada CBZ-VPA. Resultados: Níveis salivares de VPA se relacionaram linearmente com a dose diária, e a relação não linear foi encontrada em pacientes com CBZ. VPA não alterou as concentrações salivares de CBZ, porém a CBZ reduziu os níveis salivares de VPA em pacientes com terapia combinada. Pacientes refratários apresentaram altas concentrações de VPA. Os níveis de CBZ em pacientes não controlados não apresentaram diferenças significativas em relação aos pacientes controlados quando as doses diárias foram mais elevadas. Conclusão: Saliva estimulada com ácido cítrico é adequada para o monitoramento terapêutico. Níveis da droga na saliva em pacientes que não responderam ao tratamento pode ser explicado pelo transporte de efluxo generalizado.Unitermos: Concentração em saliva, carbamacepina, ácido valproico, epilepsia refratária, transportadores de efluxo.

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Section: Resultsmentioning

confidence: 99%

“…1 A widely accepted explanation to this phenomenon is the induction the drug has over intestinal enzymes, apart from the well-known hepatic enzyme induction, both of which result in lower plasma concentrations than expected when dose is increased.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid

Maldonado¹,

Fagiolino²,

Vázquez³

et al. 2008

J. epilepsy clin. neurophysiol.

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“…The magnitude of induction is dependent on the concentrations of carbamazepine and its epoxide metabolite [8]. First‐pass metabolism of carbamazepine results in approximately 30% of the dose being converted to the epoxide metabolite [9]. Therefore, the exposure of enterocytes and hepatocytes to inducers does not greatly differ between these routes of administration.…”

Section: Discussionmentioning

confidence: 99%

“…lite [9].Therefore, the exposure of enterocytes and hepatocytes to inducers does not greatly differ between these routes of administration. However, induction is also time dependent, with an estimated t1/2 of 70 h in the liver but a shorter t1/2 of 24 h in the intestine due to enterocyte turnover, which limits induction in this organ [8].…”

Section: Figurementioning

confidence: 99%

Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects

Smith¹,

Koch²,

Arya³

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Lapatinib is an orally administered tyrosine kinase inhibitor indicated for use in combination with capecitabine to treat advanced or metastatic breast cancers that overexpress ErbB2 in patients previously treated with anthracyclines, taxanes and trastuzumab.• In vitro studies have suggested that lapatinib is metabolized primarily by CYP3A4, that it is a substrate of the efflux transporter ABCB1, and that it is a modest inhibitor of both CYP3A4 and ABCB1. • However, no data regarding the in vivo metabolism of lapatinib have as of yet been reported. WHAT THIS STUDY ADDS• The in vivo pharmacokinetics of lapatinib in healthy subjects was determined in the presence of a potent inhibitor (ketoconazole) or inducer (carbamazepine) of CYP3A4.• The results indicated that systemic exposure to lapatinib was significantly altered by inhibition or induction of CYP3A4.• Thus, dose adjustments may be required when lapatinib is administered orally concomitantly with drugs that potently alter CYP3A4 activity. AIMSTo characterize the impact of potent CYP3A4 inhibition and induction on lapatinib pharmacokinetics. METHODSTwo studies were conducted in healthy subjects. One study examined the effect of ketoconazole 200 mg b.i.d. for 7 days on a single 100-mg dose of lapatinib in 22 healthy subjects. The other study examined the effect of carbamazepine titrated up to 200 mg b.i.d. over 20 days on a single 250-mg dose of lapatinib in 24 healthy subjects. RESULTSKetoconazole altered lapatinib AUC, Cmax and half-life, with geometric mean [95% confidence interval (CI)] increases of 3.57-fold (3.07, 4.15), 2.14-fold (1.74, 2.64) and 1.66-fold (1.50, 1.84), respectively, but had no effect on absorption rate. Carbamazepine altered lapatinib AUC, Cmax and absorption rate, with geometric mean (95% CI) decreases of 72% (68, 77), 59% (49, 66) and 28% (4, 46), respectively, but had no effect on half-life. CONCLUSIONSSystemic exposure to lapatinib was significantly altered by potent inhibition and induction of CYP3A4. Dose adjustments may be required when lapatinib is administered with orally administered drugs that potently alter the activity of this enzyme.

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“…Por lo tanto, el CYP3A4 sería el responsable de la BD incompleta de la droga como así también de la formación presistémica de E-CBZ. De esta manera, no sólo el aumento del Cl sistémico es responsable de la farmacocinética no-lineal de CBZ, sino también su BD dosis-dependiente (Fagiolino et al, 2006).…”

Section: A P í T U L O L a I N T E R C A M B I A B I L I D A D D E unclassified

La intercambiabilidad de medicamentos: consideraciones biofarmacéuticas y terapéuticas

Ruiz¹

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El objetivo general del presente trabajo de tesis fue contribuir en el campo de la salud pública a dar respuesta a los múltiples interrogantes planteados respecto de las garantías que ofrecen las actuales normativas en relación con la intercambiabilidad de medicamentos. Garantizar la seguridad de dichos intercambios y pautar las condiciones y/o limitaciones de su aplicación sería, no sólo un importante logro a nivel científico, sino un invaluable aporte a la sociedad que se ve directamente afectada, tanto por las falencias como por los aciertos del sistema de salud. Para ello se emplearon diversas metodologías, descriptas a continuación bajo la forma de objetivos parciales: 1. Control de calidad in vitro de todos los medicamentos empleados en los ensayos descriptos en los restantes capítulos [Capítulo 2]. 2. Estudio de la influencia del diseño experimental de los estudios de bioequivalencia (BE) sobre los resultados de los mismos: cómo influye el diseño estadístico a la hora de tomar la decisión BE/No BE entre diferentes formulaciones de un mismo medicamento [Capítulo 3]. 3. Evaluación de la capacidad de los estudios clásicos de BE, exigidos por los entes regulatorios (BEM), para garantizar la intercambiabilidad de dos formulaciones conteniendo el mismo principio activo en la misma dosis [Capítulo 4]. 4. Análisis de una de las consecuencias de los estudios de BE: el problema de la transitividad. Es decir, qué efecto tiene sobre la intercambiabilidad de medicamentos el hecho de que todos los productos presentes en el mercado con un determinado principio activo hayan demostrado su BE respecto a un mismo producto de referencia pero no entre ellos [Capítulo 5]. 5. Análisis del desempeño de diversos métodos de comparación de perfiles de disolución in vitro. Por ello se trabajó con drogas clase II del BCS (CBZ, PHT y OxCBZ), para las cuales se espera que la disolución sea la etapa limitante en el proceso de absorción. El análisis se orientó al caso de comparaciones entre productos de distintas marcas con igual principio activo, como herramienta predictiva de los resultados in vivo (caso de las bioexenciones) [Capítulo 5]. 6. Estudio del desempeño y la idoneidad de la saliva como fluido biológico de análisis en estudios de biodisponibilidad relativa (BDR) [Capítulo 6].

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Systemic and presystemic conversion of carbamazepine to carbamazepine-10,11-epoxide during long term treatment

Cited by 14 publications

References 9 publications

Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid

Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid

Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects

La intercambiabilidad de medicamentos: consideraciones biofarmacéuticas y terapéuticas

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