Toxicological Sciences, Vol 48, 230-239, Copyright © 1999 by Society of Toxicology
DK Hansen, JB LaBorde, KS Wall, RR Holson and JF Young
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.
ARTICLES
Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in rats
Division of Genetic and Reproductive Toxicology, Department of Health and Human Services, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72079-9502, USA.
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