ABSTRACT
BACKGROUND: Propofol biotransformation occurs in the liver via hydroxylation by CYP450 enzymatic complex and by glucuronidation, however extra-hepatic metabolism has also been described. OBJECTIVES: To better understand the metabolic pathways involved in propofol biotransformation, the expression of CYP1A1, CYP1A2, the enzymatic and non-enzymatic antioxidant activity and the amount of propofol and its non-conjugated metabolites were investigated. METHODS: Twenty-one NewZealand rabbits were allocated into three groups continuously treated for 20h. Each group received: NaCl 0.9%, vehicle (SMOFlipid) and propofol 2% (Lipuro). At the end, liver and kidney samples were collected for histopathology and immunohistochemistry and plasma for quantification of propofol and its metabolites. RESULTS: CYP1A1 and CYP1A2 were observed in zone 1 and zone 3 regions of the liver acinus. The propofol and saline groups showed a higher expression of CYP1A1 when compared to vehicle group. Propofol significantly increased CYP1A2 expression, compared to saline. CYP1A1 and CYP1A2 immunoexpression were observed in the kidney but no differences were registered between groups. CONCLUSIONS: This suggests that propofol may act as selective inhibitor of CYP1A1 and an inducer of CYP1A2 expression in different regions of the liver. Propofol seems to have an antioxidative protective effect on liver parenchyma, comparatively to the emulsion alone. In the rabbit, extra-hepatic propofol biotransformation may also occur in the kidney.
Subject(s)
Cytochrome P-450 CYP1A1/biosynthesis , Cytochrome P-450 CYP1A2/biosynthesis , Hypnotics and Sedatives/metabolism , Kidney/drug effects , Liver/drug effects , Propofol/metabolism , Animals , Hypnotics and Sedatives/pharmacology , Immunohistochemistry , Kidney/metabolism , Liver/metabolism , Propofol/pharmacology , RabbitsABSTRACT
El cáncer de pulmón no microcítico (CPNM) se diagnostica mayoritariamenteen pacientes mayores de 65 años. Los pacientes ancianos presentan una elevadacomorbilidad asociada al tratamiento antineoplásico que demanda la individualizaciónde las pautas posológicas. Las opciones de tratamiento son abundantes y elcarboplatino (CbPt) se encuentra entre los fármacos de primera línea. La dosis de CbPt se establece con la fórmula de Calvert (estándar) que requiere la medidaexacta de la función renal.El objetivo de este trabajo es aportar un modelo farmacocinético que permitaindividualizar las dosis de CbPt en ancianos con CPNM avanzado y evaluar suexactitud y precisión respecto al estándar.Los modelos farmacocinéticos para el CbPt no unido a las proteínas plasmáticas,obtenidos con las concentraciones plasmáticas de una población de 24 pacientesvarones con CPNM, indican que la edad es la covariable biométrica más estrechamenterelacionada con el aclaramiento plasmático de CbPt, sin dejar por ellode ser un factor de confusión. El error relativo medio (ERM) de la dosis ha sidopara los pacientes adultos (edad < 65 años) del 5% (1-9%) y para los pacientesancianos del 25% (19-30%). Por consiguiente, la dosificación de CbPt con la fórmulade Calvert conduce a una sobredosificación en los pacientes ancianos, produciendomayor exposición al fármaco de la deseada. El alcance clínico de estoshallazgos requiere su validación en una nueva población de pacientes
Non small cell lung cancer (NSCLC) is frequently diagnosed in patients olderthan age 65 years. Elderly patients often have comorbidities associated with theantineoplasic treatment that request individualization of the chemotherapy. Treatmentoptions are numerous and carboplatin (CbPt) is in the first line of treatment.Conventional doses of CbPt are individually adjusted applying the Calvert formulae(standar) that demands the accurate measure of renal function.The aim of this study is to develop a pharmacokinetic model in order to individualisethe dose of CbPt in elderly patients in advanced NSCLC, and to characterizeits bias and precision respect to the standard.The pharmacokinetic models for the unbound fraction of CpPt were obtainedfrom concentration-time data of ultrafiltrate plasma samples of twenty-four advancedNSCLC men patients enrolled in the study. Age was significantly related to thecarboplatin clearance, although is a confusion factor. The mean dose error, inpercentage, was 5% (1-9%) in adult patients (Age< 65 years) and 25% (19-30%) inelderly patients. Consequently, CbPt the dose regimen in enderly patients, establishedby means of Calverts formula is overestimated and the exposure to the antineoplasticis higher than desired. The clinical relevance of these results requiresthe validation of the model with a new population group
