Avaliação do potencial embriotóxico do tacrolimus (FK506) administrado a ratas wistar

Abstract

Tacrolimus is a macrolide antibiotic with immunosuppressive action, acting as a calcineurin inhibitor, that has being used as a standard drug avoiding rejection of most transplants. With the success of transplantations, which occurred mainly due to the use of immunosuppressive drugs, there was an improvement in life quality of patients. This fact, led to an increase in the number of gestations, even under continuous use of immunosuppressants. It is known that these drugs cross the placenta, leading to changes in embryo development. Body weight loss in newborns from mothers that used tacrolimus during gestation is described in literature. However, little is known about its action on blastocyst preimplantation period, being the aim of this work to assess if tacrolimus interferes with embryo development during tubaric transit and blastocyst implantation periods. Pregnant Wistar rats were randomly distributed into control C1 and C2 and treated T1, T2, T3, T4, T5 and T6. Control 1 and Treated 1, 2 and 3 received distilled water and 1, 2 and 4 mg/kg/day of tacrolimus, respectively, via oral gavage from first to fifth pregnancy day (tubaric transit period) and groups Control 2 and Treated 4, 5 and 6 received distilled water and 1, 2 and 4 mg/kg/day of tacrolimus respectively, via oral gavage from fifth to seventh day (implantation period). The clinical signs of maternal toxicity were analyzed. On 15th day, blood was collected for biochemical and hematological tests assessment, after that animals were killed. Ovaries, liver and kidneys were weighed and the corpora lutea were counted. Resorptions, live and dead fetuses were identified. Fetuses and placenta were weighed. Clinical signs of maternal toxicity were not found. During the period of tubaric transit there were no significant alteration in maternal body weight, food intake and hematological parameters. In biochemical analysis, the group treated with 4 mg/kg/day presented an increase in cholesterol, TGO and urea. In the group treated with 2 mg/kg/day there was creatinine reduction and group T1 (1mg/kg/day) showed reduction in TGO. In the period of blastocyst implantation it was not observed changes in body weight among groups. There was a decrease in food intake, during the treatment period wich was recovered after the drug administration, showing a gradative increase at food intake until the end of the experiment. An increase in food intake in the group treated with tacrolimus in the concentration of 4mg/Kg/day was shown. There were no significant alterations in hematological parameters. In biochemical analysis no alterations were found, except in the group T6 (4mg/kg/day) that presented a decrease. In the both experiments, during the period of blastocyst implantation and the tubaric transit, there were no significant alterations in maternal body, liver, kidney and ovaries weights. Were not observed significant alterations in the number of corpora lutea, live and dead fetuses, resorptions, fetuses weigh and lost in pre and pos implantation. In the groups treated with tacrolimus on the concentrations of 4mg/kg/day and 1mg/kg/day were observed a decrease of the implants number. The administration of Tacrolimus to pregnant rats during the tubal transit and implantation periods does not seem to generate any toxic effect on them.