Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity.
OBJECTIVE
The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model.


METHODS
All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining.


RESULTS
No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA.


CONCLUSIONS
Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.
D000818:Animals; D002087:Butyrates / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D000077287:Levetiracetam; D051379:Mice; D010889:Piracetam / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011760:Pyrrolidinones / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D013723:Teratogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
D002087:Butyrates; D011759:Pyrrolidines; D011760:Pyrrolidinones; D013723:Teratogens; D000077287:Levetiracetam; C028537:2-pyrrolidone; C032519:pyrrolidine; D010889:Piracetam