Pharmacokinetic analysis for assessing developmental toxicity of a new synthetic acetolactate synthase inhibitor, LGC-40863, in rats

Abstract

Effects of O-[2,6-bis[(4,6-dimethoxy-2pyrimidinyl)oxy]benzoyl]oxime (LGC-40863) on dams and embryonic development were examined at p.o. doses of 500, 1000 and 2000 mg/kg/day on days 6 to 15 of gestation in rats. No significant maternal or embryonic toxicity was observed at any of the doses. However, external fetal anomalies including brachycephaly, microcephaly, micrognathia, agnathia, lordosis and edema were observed at an incidence of 2.2% at the lowest dosage level but not at higher dosages. Because these malformations are not common as spontaneous variations in rats, we carried out a toxicokinetic study to clarify whether the fetal anomalies at 500 mg/kg are related to LGC-40863. During multiple p.o. administrations of LGC-40863 at the same doses used in the developmental toxicity study, LGC-40863 was not detected in the systemic circulation. Moreover, 3 months of multiple dosing did not alter its plasma level. In the pregnant rats receiving 500 mg/kg on 10 consecutive days of gestation, LGC-40863 was also undetectable. However, after i.v. administration, high levels of the drug were found in plasma, and these could be described by a two-compartment model. These results demonstrate that the bioavailability of LGC-40863 is negligible. To investigate a possible relevance of metabolite(s) to the fetal anomalies, we examined excretion of radioactivity after p.o. doses of 500 and 2000 mg/kg of LGC-40863 spiked with [14C]LGC-40863. For both doses, cumulative recovery up to 72 hr was approximately 80% and 9% in feces and urine, respectively, indicating dose linearity in the elimination kinetics. Overall, these toxicokinetic data suggest that the fetal anomalies observed at 500 mg/kg are not associated with LGC-40863 but are spontaneously generated. In conclusion, LGC-40863 had neither significant maternal nor developmental toxicity at any of the doses tested for p.o. exposure.