Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in rats

Abstract

Dexamethasone (DEX) has been shown to elicit growth stunting and cleft palate in rat fetuses. This investigation characterized DEX dosimetry as various pharmacokinetic parameters and evaluated their impact on developmental toxicity endpoints. DEX pharmacokinetics was evaluated as a single dose on either gestation day (GD) 9 or 14, as well as on GD 14 after multiple daily dosing from GD 9 to GD 14. An additional set of pregnant rats was dosed with DEX on GD 9 through GD 14, pharmacokinetic evaluation was conducted on GD 14 through GD 16, and teratological evaluation was conducted following sacrifice on GD 20. For all pharmacokinetic evaluations, a subcutaneous (sc) injection of 0.8 mg DEX/kg body weight together with 50 microCi 3H-DEX was administered to Sprague-Dawley rats. Blood, urine, and feces were collected for 24 or 48 h. At GD 20 sacrifice, maternal tissues as well as fetal brain and liver samples were collected as part of the laparotomy. All samples were assayed using scintillation spectrometry. DEX pharmacokinetic parameters remained similar whether dosing occurred early (GD 9) or late (GD 14) in organogenesis, or dosing occurred on multiple sequential days (GD 9-14). DEX produced maternal and fetal weight loss, fetal lethality, and cleft palate. DEX a-half-life was positively correlated with the percentage of implants affected [(number of non-live + number with cleft palate)/number of implants]/litter. Neither the area under the concentration-time curve (AUC), the maximum maternal plasma concentration (Cmax), nor the terminal phase beta-half-life correlated with any fetal outcome parameters. The correlation between the percentage of the litter that was affected and half-life was improved if AUC was added in a stepwise multiple regression. These data suggest that the length of time that DEX is present in the maternal plasma at a sufficiently high concentration (i.e., slower tissue distribution of DEX) appears to be important in determining the risk of an adverse outcome in the offspring.

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

“…The effect of dexamethasone was transient lapsing after 4 h of treatment. This relatively short-lasting effect as compared to longer biological activity [45] and terminal half-life [46] reported in rats might be due to species differences in dexamethasone pharmacokinetics [46]. Besides its established anti-inflammatory properties, dexamethasone anticonvulsant effect may be mediated by its ability to reverse the increased serum corticosterone concentrations, which are elicited by elevated IL-1β brain levels via activation of the hypothalamic-pituitary adrenal axis (HPA) axis [47,48].…”

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

“…We found that a conventional two-compartment model with a zero-order absorption process best described the pharmacokinetics of DEX in our study. Both onecompartment [33,34] and two-compartment models [35] have been found to best describe DEX plasma concentration profiles [34] . The first-order absorption of DEX has been reported previously [36] .…”

Dexamethasone suppresses the expression of multiple rat carboxylesterases through transcriptional repression: Evidence for an involvement of the glucocorticoid receptor

“…Apparently, the persistent suppression in rats was not due to insufficient exposure compared with the concentrations used in cell culture. It was reported that rats dosed at 0.8 mg/kg produced a C max of 682 ng/ml in the blood, equivalent to ~1.7 μM (Hansen et al, 1999). Based on this estimation, a single ip injection of 50 mg/kg would produce a blood concentration of ~62.5 μM.…”