Efeitos do hipotireoidismo induzido experimentalmente no comportamento depressivo e na farmacocinética da venlafaxina em ratos wistar adultos

Abstract

Hypothyroidism is a high global incidence disorder, and its most common cause is dietary iodine deficiency. Individuals with hypothyroidism usually develop comorbidities related to the lack of TH; the depression is example of one these diseases. In some cases, patients with depression do not respond well to treatment with antidepressant drugs, and a possible cause for this fact is the lack of thyroxine hormone replacement (T4). Therefore, the present work proposes to evaluate whether experimentally induced hypothyroidism, with or without T4 replacement, alters venlafaxine pharmacokinetics, assessing whether there is a relationship between hypothyroidism and depressive behavior in male Wistar rats. The evaluation was made by comparing rats with experimental induction of hypothyroidism in two different ways, by thyroidectomy (Tx) and methimazole treatment (MMI), with and without T4 hormone replacement (20μg /kg/day v.o). Control animals of the surgical procedure were those submitted to sham surgery (SHAM). In order to characterize the hypothyroidism, the free T4 and thyroid stimulating hormone (TSH) dosages were measured, as well as the measurement of the thyroid axis function related tissue masses [adenohypophysis, brown adipose tissue (TAB), perigonadal white adipose tissue (TAM) and thyroid)]. For the depressive behavior evaluation, forced swimming and sucrose ingestion tests were performed. Regarding pharmacokinetics, blood samples were collected for venlafaxine analysis through cannulation at time 0-12h; The dosages were performed in gas chromatography coupled with mass spectrometry, in a method developed and validated according to ANVISA standards. According to the results, the groups without hormone replacement, Tx and MMI, and the group Tx with replacement presented lower free T4 plasma concentrations compared to the SHAM group, respectively (0,3; 0,3; 1,1 vs. 1,7ng/dL); the MMI group with replacement presented T4 values similar to SHAM. On the mass analysis of the adenohypophysis, thyroid and TAM; reduced values were observed for TAM in the non-replacement groups, Tx and MMI, compared to SHAM, respectively (73,4; 75,9 vs. 12,6mg/100g) and increased for the adenohypophysis (3,4; 3,1 vs. 2,2mg/100g) and thyroid (14,0 vs. 4,7mg/100g MMI vs. SHAM). Together, these results point to the correct functioning of the negative feedback mechanism in the hypothalamic-pituitary-thyroid axis. Concerning depressive behavior, only the non-replacement MMI group had a longer immobility time (153,6 vs. 86,9s) and a lower preference for sucrose (80,0 vs. 94,8%) compared to SHAM. Evaluation of pharmacokinetic parameters showed changes in the Tx group without hormone replacement, such as increased AUC (440,7 vs. 1037,5ng.h / mL), half-life (2,9 vs. 1,3h), maximum concentration (880,4 vs. 432,2ng / mL), and decreased clearance (4,2 vs. 19,8L/h/kg) compared to the SHAM group. Based on the results, it can be concluded that the depressive-like behavior was characterized in the MMI group without hormone replacement and the thyroidectomy-based induction model was able to alter the pharmacokinetic parameters of venlafaxine, suggesting that the lack of HT present in hypothyroidism interferes with the pharmacokinetics of venlafaxine.