Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in rats.
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.
Hansen
D K
DK
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.
LaBorde
J B
JB
Wall
K S
KS
Holson
R R
RR
Young
J F
JF
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000633:toxicity; D003907:Dexamethasone / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D013723:Teratogens; D003907:Dexamethasone