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Influence of inflammation on the kinetic disposition, metabolism and enantioselectivity of chiral drugs in patients with psoriasis, multiple sclerosis or systemic sclerosis

Abstract

Psoriasis, multiple sclerosis and systemic sclerosis are auto immune diseases characterized by chronic inflammatory state and associated with increasing cytokines expression. Cytokines can alter the expression and activity of CYP and modify the metabolism of drugs. Cytokines can also influence the intestinal, hepatic and brain expression of P-glycoprotein (P-gp) involved on transportation of many drugs, modifying their bioavailability, distribution and clearance. These changes can contribute to drug response variability as well as in the incidence of adverse effects.This study aims to evaluate the kinetic disposition and metabolism of the chiral drugs venlafaxine and cyclophosphamide in patients with inflammation associated to the disease. Cyclophosphamide is a CYP substrate and venlafaxine is a CYP and P-gp substrate. In the Part I of the present project will be evaluated the influence of inflammation on the kinetic disposition, metabolism and enantioselectivity on the drug interaction venlafaxine-paroxetine in patients with psoriasis and in healthy volunteers genotyped for CYP2D6 and monitored for plasma cytokynes. Thirteen adult patients with psoriasis and thirteen healthy volunteers will be investigated in a crossover and randomized study developed in two phases separated by two weeks washout period. Patients and healthy volunteers will be treated with a single oral dose of 150 mg racemic venlafaxine or will be pretreated during 10 days with 20 mg paroxetine/day prior to administration of a single oral dose of 150 mg racemic venlafaxine. In the Part II of the present project will be investigated the kinetic disposition of cyclophosphamide enantiomers and their metabolites in patients with multiple sclerosis and systemic sclerosis undergoing hematopoietic stem cell transplantation with the aim to evaluate the clinical relevance of therapeutic drug monitoring. Steady-state plasma concentrations of cyclophosphamide enantiomers and their metabolites will be correlated to clinical parameters of disease remission, adverse effects and cytokines plasma concentrations. Ten patients with multiple sclerosis and ten patients with systemic sclerosis undergoing hematopoietic stem cell transplantation and genotyped for CYP2B6, CYP2C9 and GST will be investigated. Patients will be treated with the conditioning regimen composed by 50 mg/kg/day intravenous cyclophosphamide during 4 days. Pharmacokinetics parameters will be calculated using the plasma concentrations versus time employing the software WinNonLin. Statistical analysis will be conducted using non parametric tests. (AU)

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