Pharmacokinetics and analysis of transplacental distribution of fluoxetine and its metabolite in pregnant women with gestational Diabetes mellitus

Abstract

The development and / or exacerbation of clinical depression during pregnancy may lead to potential risks for both mother and fetus. Fluoxetine is the most widely used drug in the treatment of depressive states during pregnancy.Diabetes mellitus may act by inhibiting or inducing some CYP enzymes, altering the expression of its isoforms. The influence of Gestational Diabetes Mellitus in the kinetic disposition and metabolism of drugs used in clinical practice is still subject of scarce thorough evaluation in the literature. Few reports exploring the impact of this disease on the pharmacokinetics and placental transfer of antidepressants, especially of fluoxetine and its metabolite, which is the focus of this study.Objectives: Analysis of the influence of gestational diabetes mellitus on pharmacokinetics and placental transfer rate of fluoxetine and norfluoxetine (active metabolite) in pregnant women. Methods: Nine nondiabetic pregnant women (group 1) and nine pregnant women with GDM (group 2) will be assessed, all in the third trimester of pregnancy. All will receive a single dose of 20 mg of fluoxetine administered orally in two separate occasions, the first being in the third trimester (32 weeks) and second on the day of delivery. After drug administration in the first occasion, serial maternal blood samples (10 mL) will be collected to assess the concentration of the fluoxetine enantiomers at time zero, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24 , 48, 72, 96, 168, 336, 504 and 672 hours. Urine samples (3 mL) will be collected at 24, 48, 72, 96, 168, 336, 504 and 672 hours. On delivery day, after receiving the medication, a maternal blood sample will be collected mother at the time of birth. Blood samples from the umbilical vessels and intervillous space, plus amniotic fluid sample will be also collected for assessing placental transfer of the drug. Twenty-four hours after delivery, will be collected a breast milk sample (3 mL) and urine sample for evaluation of the drug excretion. After the collection of biological samples, chromatographic analysis will be performed to determine the concentrations of fluoxetine and norfluoxetine and, consequently, to evaluate the pharmacokinetic parameters and the rate of placental transfer. (AU)