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[Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (I)--Fertility study in rats by
M Shinomiya1, K Imamura, K Izumi
1Drug Safety Research Laboratory, Taiho Pharmaceutical Co., Ltd, Tokushima, Japan.
Abstract:
S-1 is a newly developed antineoplastic agent consisting of the mixture of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. As part of a reproductive and developmental toxicity study of S-1, a fertility study was carried out in Sprague-Dawley rats. Twenty-four male rats were administered S-1 orally starting at 64 days before mating and 24 female rats were administered S-1 orally from 15 days before mating to day 7 of pregnancy at doses of 0, 1, 4, or 7 mg/kg/day (as a dose of FT) in order to investigate the effect of S-1 on the reproductive ability and development of embryos and fetuses. There were no dose-related changes in clinical signs. Body weight gains and food consumption were decreased and were associated with the decreased weights of thymus, testis and epididymis in male rats receiving S-1 at the 7 mg/kg/day group. In females, the only organ affected was the kidney at 7 mg/kg/day. There were no dose-related changes in copulation, fertility, pre-implantation loss and implantation. Decreases in live fetal body weight and retardation of fetal ossification were observed in the 7 mg/kg/day group. There were no dose-related changes in post-implantation loss, and no fetal malformations were observed. The results suggest that the non-observed effects dose level of S-1 for general toxicity in male and female rats in 4 mg/kg/day, for reproductive toxicity in adults is more than 7 mg/kg/day, and for developmental toxicity in utero is 4 mg/kg/day.
Insights
S-1, an antineoplastic agent, showed no adverse reproductive effects in rats at doses up to 7 mg/kg. Developmental toxicity, including reduced fetal weight, was observed at 7 mg/kg, suggesting a 4 mg/kg no-observed-effect level for developmental toxicity.
Area of Science:
- Pharmacology and Toxicology
- Reproductive Toxicology
- Developmental Toxicology
Context:
- S-1 is a novel antineoplastic agent comprising tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate.
- Reproductive and developmental toxicity studies are crucial for assessing the safety of new pharmaceutical agents.
Purpose:
- To evaluate the effects of S-1 on reproductive ability and embryonic/fetal development in Sprague-Dawley rats.
- To determine the no-observed-effect dose levels for general, reproductive, and developmental toxicity of S-1.
Summary:
- Rats received oral S-1 (0, 1, 4, or 7 mg/kg/day) before and during mating/gestation.
- General toxicity (decreased body weight, organ weights) occurred at 7 mg/kg in males and kidney effects in females.
- No adverse effects on fertility or implantation were noted; however, decreased fetal body weight and delayed ossification were observed at 7 mg/kg.
Impact:
- Identifies a no-observed-effect dose level of 4 mg/kg for general and developmental toxicity.
- Suggests reproductive toxicity in adults occurs at doses greater than 7 mg/kg.
- Provides critical safety data for S-1, informing its clinical application and risk assessment.