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Published on: June 17, 2015
Developmental and reproduction toxicity studies of Biolimus A9 in SD rats
Shidong Qiu1, Yang Liu2, Yuanhang Pan3
1Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences. Jinan 250117, China.
Abstract:
Biolimus A9 (BA9) is a novel rapamycin derivative. In this report we evaluated the potential toxicity of BA9 in a developmental and reproduction toxicity study (segment Ⅰ, Ⅱ, Ⅲ). In segment I, body weight gains in F0 rats receiving 0.80 mg/kg/day were decreased. A lower fertility index of males was observed and females failed to become pregnant in the 0.80 mg/kg/day group. The number of live fetuses and implantations were decreased while the number of dead fetuses, resorptions, and implantation losses were increased in the 0.12 mg/kg/day group. In segment Ⅱ, maternal toxicity: body weight gains in F0 females receiving 0.036 and 0.090 mg/kg/day group were decreased. Embryo toxicity: In the 0.090 mg/kg/day group, weights and body lengths of fetuses were decreased, the numbers of viable fetuses was decreased and resorbed fetuses increased. Teratogenic effects: The percent of visceral variations and skeletal variations were both increased in the 0.090 mg/kg/day group. In segment Ⅲ, dosing F0 rats with BA9 at dose levels of 0.12 and 0.80 mg/kg/day resulted in reproductive and maternal toxicity, consisting of prolonged labor, dystocia, increased mortality, along with reductions in lactation food consumption. F1 rats in the 0.12 mg/kg/day group showed reproductive and developmental toxicity consisting of body weight decreases, decreased food consumption after weaning and a reduction in the gestation index of pregnant rats. Based on these findings, the no-observed-adverse-effect-level (NOAEL) of BA9 toxicity in segment Ⅰ and Ⅲ was 0.02 mg/kg/day. The NOAEL in segment Ⅱ was 0.015 mg/kg/day.
Insights
Biolimus A9 (BA9), a rapamycin derivative, showed developmental and reproductive toxicity in rats, impacting fertility, fetal development, and maternal health. The no-observed-adverse-effect-level (NOAEL) varied by study segment, with the lowest being 0.015 mg/kg/day.
Area of Science:
- Pharmacology
- Toxicology
- Reproductive Biology
Background:
- Biolimus A9 (BA9) is a novel derivative of rapamycin.
- Rapamycin derivatives are used in various medical applications, necessitating toxicity assessments.
Purpose of the Study:
- To evaluate the potential developmental and reproductive toxicity of Biolimus A9 (BA9) in a comprehensive study.
- To determine the no-observed-adverse-effect-level (NOAEL) for BA9 toxicity across different study segments.
Main Methods:
- Conducted a three-segment developmental and reproduction toxicity study (Segments I, II, III) in rats.
- Administered varying doses of BA9 to assess effects on fertility, maternal health, embryo-fetal development, and offspring development.
Main Results:
- BA9 exposure led to decreased body weight gain, reduced fertility, and increased fetal loss in Segment I.
- Maternal toxicity, embryo toxicity (decreased fetal weight/length, increased resorptions), and teratogenic effects (visceral/skeletal variations) were observed in Segment II.
- Reproductive and maternal toxicity (prolonged labor, mortality, reduced lactation) and F1 offspring toxicity were noted in Segment III.
Conclusions:
- Biolimus A9 exhibits dose-dependent developmental and reproductive toxicity in rats.
- The no-observed-adverse-effect-level (NOAEL) for BA9 was determined to be 0.02 mg/kg/day for Segments I and III, and 0.015 mg/kg/day for Segment II.
