Reproductive toxicity study with a novel deoxyguanosine analogue (Metacavir) in pregnant SD rats

Abstract

Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo-fetal developmental toxicity and teratogenicity were studied in pregnant Sprague-Dawley rats after intragastric administration of Metacavir (200, 100, 50, 0 mg/kg body weight) during the first 6–15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6–20 pregnant days were significantly different (P<0.01, P<0.05). Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group (P<0.05), while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/(kg·d) (i.e., 40 times the effective dose in rats), Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/(kg·d) there is no teratogenic side effects.

Keywords

deoxyguanosine analogue / Metacavir / pregnancy / maternal toxicity / embryo toxicity / teratogenicity

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Acknowledgements

The research was supported by the Twelfth Five-Year Plan of National Science and Technology Major Project (2011ZX09301-001), Sichuan Province Basic Research Program (2011JY005), the Youth Innovation Research Team Foundation of Sichuan Province Science and Technology Bureau (2013TD0015) .

Compliance with ethics guidelines

Qihui Luo, Zhengli Chen, Anchun Cheng, Mingshu Wang, Jing Fang, Xi Peng, and Li Tang declare no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

RIGHTS & PERMISSIONS

2015 Higher Education Press and Springer-Verlag Berlin Heidelberg