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Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the
Abstract:
The dosage-regimen-dependent teratogenicity as well as plasma and tissue levels of the antiepileptic drug valproic acid (VPA) were studied in the mouse by comparing various injection regimens and infusion of the drug via implanted osmotic minipumps. Concentrations of 225-248 micrograms VPA/ml maternal plasma (about 2X above the therapeutic concentration range) and 70-75 micrograms VPA/g gestational material (on gestation Day 8) resulted in a significant incidence of neural tube defects (exencephaly in the mouse). Similar effects were produced if those concentrations were reached several times after multiple injections or by steady-state application via implanted pumps. A single injection was less effective than multiple injections, although drug accumulation did not occur. The doses (or area under the concentration-time curve values) did not correlate with the teratogenic response of the different administration regimens: much higher (factor 10) doses were needed with the infusion regimen to produce exencephaly rates comparable to those obtained with the injection regimen. The pattern of embryotoxicity was also schedule dependent: steady-state concentrations produced predominantly embryolethality and fetal weight retardation, while intermittent injections produced a high incidence of exencephaly (up to 60% of live fetuses). The dose of VPA (and the areas under the concentration-time curves) correlated with the embryolethality and fetal weight retardation of the drug, while the peak or steady-state concentrations reached in mother and gestational material correlated with the incidence of neural tube defects.
Insights
Valproic acid (VPA) teratogenicity in mice depends on administration schedule, not total dose. Peak VPA concentrations are linked to neural tube defects, while cumulative exposure causes other toxicities.
Area of Science:
- Pharmacology
- Developmental Toxicology
- Neuroscience
Background:
- Antiepileptic drugs, including valproic acid (VPA), are crucial for managing seizures.
- Understanding VPA's teratogenic potential is vital for patient safety during pregnancy.
- Dosage and administration methods can significantly influence drug efficacy and toxicity.
Purpose of the Study:
- To investigate the relationship between VPA dosage regimens, plasma/tissue levels, and teratogenicity in mice.
- To determine if dose or concentration is the primary driver of VPA-induced developmental defects.
- To compare the teratogenic effects of intermittent injections versus continuous infusion of VPA.
Main Methods:
- Administered VPA to mice via multiple injection regimens and continuous infusion using osmotic minipumps.
- Measured VPA concentrations in maternal plasma and gestational material at specific time points.
- Assessed teratogenic outcomes, including neural tube defects (exencephaly), embryolethality, and fetal weight retardation.
Main Results:
- Specific VPA plasma (225-248 µg/ml) and tissue (70-75 µg/g) concentrations induced significant neural tube defects (exencephaly).
- Continuous infusion required 10-fold higher doses than injections to achieve comparable rates of exencephaly.
- Intermittent injections led to a higher incidence of exencephaly, whereas steady-state concentrations resulted in more embryolethality and fetal weight retardation.
Conclusions:
- VPA's teratogenicity, particularly neural tube defects, is strongly dependent on the administration schedule and resulting peak concentrations, not solely on the total dose or area under the curve.
- The pattern of VPA embryotoxicity (neural tube defects vs. growth retardation/lethality) is schedule-dependent.
- These findings highlight the importance of considering drug administration dynamics in assessing teratogenic risk.