In vitro embryotoxicity of carbamazepine and carbamazepine-10, 11-epoxide.
Carbamazepine (Tegretol, CBZ) is an anticonvulsant drug that is very effective in the treatment of tonic-clonic seizures and is gaining acceptance as a treatment for various psychiatric disorders. The drug is embryotoxic in rodents and has been reported to produce neural tube defects in approximated 1% of prenatally exposed human offspring. It is metabolized by the cytochrome P-450 system to a stable, pharmacologically active epoxide intermediate, carbamazepine-10, 11-epoxide. It is currently unknown whether the parent compound, the epoxide intermediate or some other metabolite is the embryotoxic agent. The present study was designed to determine the embryotoxicity of CBZ and its epoxide intermediate (CBZ-E) in a rodent whole embryo culture system. Rat embryos were cultured beginning on day 9 of gestation (GD 9), and mouse embryos were cultured beginning in GD 8. All embryos were cultured for 48 hr in medium containing various concentrations of either CBZ or CBZ-E. Mice were more sensitive to the effects of CBZ than were rats. The parent compound was embryotoxic to mouse embryos at concentrations as low as 12 micrograms, but it was only embryotoxic at 60 micrograms/ml to rat embryos. CBZ-E was not embryotoxic to either species at concentrations as high as 48 micrograms/ml. These results suggest that the parent compound is the embryotoxic agent and that the epoxide intermediate plays no role in the drug's embryotoxic mechanism.
National Center for Toxicological Research, Food Drug Administration, Department of Health and Human Services, Jefferson, Arkansas 72079-9502, USA.
D K
DK
Hansen
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SL
Dial
K K
KK
Terry
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TF
Grafton
D000818:Animals; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000633:toxicity*; D051379:Mice; D051381:Rats; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D002220:Carbamazepine; C012227:carbamazepine epoxide