Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats.
BACKGROUND
Matrix metalloproteinases (MMPs) play key roles in remodeling of the extracellular matrix during embryogenesis and fetal development. The objective of this study was to determine the effects of prinomastat, a potent selective MMP inhibitor, on fetal growth and development.


METHODS
Prinomastat (25, 100, 250 mg/kg/day, p.o.) was administered to pregnant female Sprague-Dawley rats on gestational days (GD) 6-17. A Cesarian section was carried out on GD 20 and the fetuses were evaluated for viability and skeletal and soft tissue abnormalities.


RESULTS
Prinomastat treatment at the 250 mg/kg/day dose produced a decrease in body weight and food consumption in the dams. A dose-dependent increase in post-implantation loss was observed in the 100 and 250 mg/kg/day-dose groups, resulting in only 22% of the dams having viable litters for evaluation at the 250 mg/kg/day dose. Fetal skeletal tissue variations and malformations were present in all prinomastat treated groups and their frequency increased with dose. Variations and malformation in fetal soft tissue were also increased at the 100 and 250 mg/kg/day doses. Prinomastat also interfered with fetal growth of rat embryo cultures in vitro.


CONCLUSIONS
These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.
Younis
Husam S
HS
Worldwide Safety Sciences, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. husam.younis@pfizer.com
Jessen
Bart A
BA
Wu
Ellen Y
EY
Stevens
Gregory J
GJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities; D004435:Eating / Q000187:drug effects; D046149:Embryo Culture Techniques; D020964:Embryo Loss / Q000139:chemically induced; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000002:abnormalities* / Q000187:drug effects / Q000201:enzymology; D061965:Matrix Metalloproteinase Inhibitors; D009929:Organ Size / Q000187:drug effects; D009930:Organic Chemicals / Q000493:pharmacokinetics / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; C113282:prinomastat