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Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in rats
D K Hansen1, J B LaBorde, K S Wall
1Division 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.
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.
Insights
Dexamethasone (DEX) exposure during pregnancy can cause fetal developmental toxicity. The drug's half-life, not peak concentration, correlated with adverse outcomes like cleft palate, suggesting prolonged exposure is key.
Area of Science:
- Pharmacology
- Developmental Toxicology
- Teratology
Background:
- Dexamethasone (DEX) is known to cause fetal growth stunting and cleft palate in rats.
- Understanding DEX pharmacokinetics is crucial for evaluating its developmental toxicity.
Purpose of the Study:
- To characterize DEX dosimetry and its impact on developmental toxicity endpoints in rat fetuses.
- To evaluate the relationship between DEX pharmacokinetic parameters and teratogenic effects.
Main Methods:
- Pregnant Sprague-Dawley rats were administered subcutaneous injections of 0.8 mg/kg 3H-DEX on specific gestation days (GD 9 or 14) or multiple days (GD 9-14).
- Pharmacokinetic parameters (blood, urine, feces) were measured over 24-48 hours.
- Teratological evaluations were conducted on GD 20, including assessment of maternal and fetal tissues, brain, and liver.
Main Results:
- DEX pharmacokinetic parameters were consistent across different dosing timings and durations.
- DEX exposure resulted in maternal and fetal weight loss, fetal lethality, and cleft palate.
- DEX half-life showed a positive correlation with the percentage of affected implants per litter.
Conclusions:
- The duration of DEX presence in maternal plasma, rather than peak concentration, appears critical for developmental toxicity.
- Slower tissue distribution of DEX may increase the risk of adverse outcomes in offspring.
- Pharmacokinetic modeling, incorporating AUC and half-life, can improve prediction of DEX-induced developmental toxicity.