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Developmental Outcome of Levetiracetam, Its Major Metabolite in Humans, 2‐Pyrrolidinone N ‐Butyric Acid, and Its Enantiomer ( R )‐α‐ethyl‐oxo‐pyrrolidine Acetamide in a Mouse Model of Teratogenicity
Author(s) -
Isoherranen Nina,
Spiegelstein Ofer,
Bialer Meir,
Zhang Jing,
Merriweather Michelle,
Yagen Boris,
Roeder Michael,
Triplett Aleata A.,
Schurig Volker,
Finnell Richard H.
Publication year - 2003
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.2003.21503.x
Subject(s) - metabolite , chemistry , anticonvulsant , pharmacology , medicine , endocrinology , biochemistry , epilepsy , psychiatry
Summary: Purpose: 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 )‐α‐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 8½ to 12½. 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 18½, 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.