Transplacental metabolism of dexamethasone and cortisol in the late gestational age rhesus monkey (Macaca mulatta)

Abstract

The synthetic glucocorticoid dexamethasone (DEX) and endogenous cortisol were compared in 2 groups of pregnant monkeys of gestational age 143-148 days. In group I, a fetal intraplacental vein and a maternal femoral vessel were catheterized. 3H-Cortisol and 14C-DEX were administered intravenously along with 0.2 mg/kg unlabelled DEX to the mother. Blood and tissue samples were collected to 3 h and urine and feces to 96 h. In group II, 4 of the 7 animals were predosed with DEX 10 mg/kg s.c. for 3 days prior to surgery. The fetus was removed by cesarean section and the in situ placenta was perfused via the umbilical arteries at 15 ml/min X 8 min with 3H-cortisol/14C-DEX in Hanks' balanced salt solution. Samples were taken from the umbilical vein and uterine vein. In group I, HPLC analysis of paired maternal and fetal plasma samples taken at 10, 20, 60, 120 and 180 min after dosing indicated that the F/M DEX ratio was significantly greater than the F/M cortisol ratio. In fetal lung and liver tissues analyzed, less than 2% of the cortisol remained unmetabolized by 3 h, whereas greater than or equal to 76% DEX remained as parent compound. There was no significant difference between the percentage of DEX (83 +/- 7%) and cortisol (73 +/- 3%) recovery in maternal urine and feces. In group II, HPLC analysis of paired umbilical vein and uterine vein samples at 2, 4 and 8 min showed that by 8 min 24% of cortisol was converted to cortisone by the uteroplacenta, but only 2.5% of DEX was converted to a metabolite. In DEX-pretreated animals both uterine vein and umbilical vein samples indicated an increase in cortisol to cortisone conversion. A significant increase in DEX metabolism was evident in the uterine vein samples but not the umbilical vein. These data indicate that the fetus is exposed to a higher proportion of DEX than cortisol and that the uteroplacenta plays a larger role in cortisol than in DEX metabolism. In addition, these data suggest that DEX pretreatment enhances the ability of the uteroplacenta to convert cortisol to cortisone.