Disposition of synthetic glucocorticoids: II. Dexamethasone in parturient women

Abstract

The plasma level: time profile for dexamethasone after dexamethasone phosphate 8 mg by intravenous bolus (n = 6) or intramuscular injection (n = 6) to pregnant women near term who were to undergo cesarean section was determined by high-performance liquid chromatography. Although pregnancy did not affect the terminal half-life (mean, 142 min; n = 10), the estimate of total plasma clearance was greater in pregnant (559 ml/min) than in nonpregnant women (243 ml/min). The umbilical/maternal venous plasma level ratios of dexamethasone rose with time from last dose to delivery, toward a plateau value of about 0.45. Plasma binding was not different between blood from pregnant (66.6% bound, n = 11) and nonpregnant women (68.1% bound, n = 6) but was lower in umbilical vein blood (60.8% bound, n = 11). Blood/plasma level ratio was higher in maternal (0.92, n = 7) and umbilical vein blood (1.04, n = 7) than in blood from nonpregnant subjects (0.81, n = 12). We conclude that the fetus is a slowly equilibrating compartment for dexamethasone and that the transplacental dexamethasone concentration gradient as well as the increased total clearance in the mother near parturition are most likely attributable to metabolic clearance by the placenta.

Area/Moment and Compartmental Modeling of Pharmacokinetics During Pregnancy: Applications to Maternal/Fetal Exposures to Corticosteroids in Sheep and Rats

“…Minor differences in the maternal and fetal plasma protein binding of these steroids in human (16,20,21), sheep (22) and rat (19) plasma do not explain the maternal/ fetal concentration gradient. This indicates that some disposition process restricts the fetal access of exogenous corticosteroids in these species.…”

“…Corticosteroid pharmacokinetic profiles after maternal drug administration in humans (16,17), sheep (5,18), and rats (19) show total fetal to maternal concentration ratios of less than 1 (Յ0.45). Minor differences in the maternal and fetal plasma protein binding of these steroids in human (16,20,21), sheep (22) and rat (19) plasma do not explain the maternal/ fetal concentration gradient.…”

Differential Effects of Pregnancy on Mineralocorticoid and Glucocorticoid Receptor Availability and Immunoreactivity in Cortisol Feedback Sites

“…Studies have demonstrated that synthetic glucocorticoids suppress plasma cortisol [1, 3, 4, 5]and ACTH [5]less efficaciously during pregnancy in humans. Although this suggests that increases in resting plasma cortisol concentration are caused by a reduced feedback suppression of ACTH [1], increases in adrenal responsiveness to ACTH [1]and/or increase in clearance of synthetic glucocorticoids [6]could also account for the apparent decrease in feedback sensitivity in humans.…”

Hierarchical Maturation of Innate Immune Defences in Very Preterm Neonates

“…The use of antenatal corticosteroids (ANS) in mothers of preterm infants delivered before 34 weeks of gestation is standard practice in perinatal medicine [6]. Significant immune attenuation can also be observed in mononuclear cells exposed in vitro to corticosteroid equivalents comparable to levels measured in serum of pregnant women after a standard ANS treatment [7,8,9,10]. However, when examining infants exposed to ANS, no effects were detected on cord blood IL-6 responses [9].…”