PHARMACOKINETIC ANALYSIS FOR ASSESSING DEVELOPMENTAL TOXICITY OF A NEW SYNTHETIC ACETOLACTATE SYNTHASE INHIBITOR, LGC-40863, IN RATS

Effects of O-[2,6-bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoy l]oxime (LGC-40863) on dams and embryonic development were examined at p.o. do ses of 500, 1000 and 2000 mg/kg/day on days 6 to 15 of gestation in ra ts. No significant maternal or embryonic toxicity was observed at any of the doses. However, external fetal anomalies including brachycephal y, microcephaly, micrognathia, agnathia, lordosis and edema were obser ved at an incidence of 2.2% at the lowest dosage level but not at high er dosages. Because these malformations are not common as spontaneous variations in rats, we carried out a toxicokinetic study to clarify wh ether the fetal anomalies at 500 mg/kg are related to LGC-40863. Durin g multiple p.o. administrations of LGC-40863 at the same doses used in the developmental toxicity study, LGC-40863 was not detected in the s ystemic circulation. Moreover, 3 months of multiple dosing did not alt er its plasma level. In the pregnant rats receiving 500 mg/kg on 10 co nsecutive days of gestation, LGC-40863 was also undetectable. However, after i.v. administration, high levels of the drug were found in plas ma, and these could be described by a two-compartment model. These res ults demonstrate that the bioavailability of LGC-40863 is negligible. To investigate a possible relevance of metabolite(s) to the fetal anom alies, we examined excretion of radioactivity after p.o. doses of 500 and 2000 mg/kg of LGC-40863 spiked with [C-14]LGC-40863. For both dose s, cumulative recovery up to 72 hr was approximately 80% and 9% in fec es and urine, respectively, indicating dose linearity in the eliminati on 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 sign ificant maternal nor developmental toxicity at any of the doses tested for p.o. exposure.