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© 1996 Oxford University Press

research-article

Developmental Toxicity Study of Mangafodipir Trisodium Injection (MnDPDP) in New Zealand White Rabbits

WILLIAM F. BLAZAK*, GEORGE L. BROWN*, TIM J. B. GRAY{dagger}, KIMBERLEY A. TREINEN{ddagger},1 and KEVIN H. DENNY§

*Nycomed Inc. Wayne. Pennsylvania 19087 {dagger}Sanofi Research Division. Sanofi Winthrop Inc., Alnwick Research Centre Alnwick, Northumberland NE66 2JH United Kingdom {ddagger}Sanofi Winthrop Inc. Collegeville, Pennsylvania 19426 §International Research and Development Corporation Mattawan, Michigan 49071

Received September 25, 1995; accepted May 2, 1996

Mangafodipir trisodium injection (MnDPDP) is an intravenously administered manganese chelate undergoing clinical evaluation for magnetic resonance imaging contrast enhancement of the hepatobiliary system. The anticipated single clinical dose for adults is 5 µmol/kg body wt. MnDPDP, as well as the inorganic salt, MnCl2 was previously shown to induce a specific syndrome of skeletal abnormalities in rats. The syndrome malformations included angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. The objective of the present study was to assess the developmental toxicity of MnDPDP in a second mammalian species, the New Zealand White rabbit. MnDPDP was intravenously administered daily to groups of rabbits (22 per group) on Days 6 through 18 of pregnancy at doses of 0 (saline), 5, 20, 40, and 60 µmol/kg MnDPDP. Fetuses were examined on Day 29 of pregnancy for external, visceral, and skeletal abnormalities. Treatment with MnDPDP did not result in overt symptoms of maternal toxicity, and there were no significant effects on maternal body weight gains or feed consumption. The maternal no-observed-adverse-effect level (NOAEL), therefore, was 60 µmol/kg MnDPDP. Treatment with MnDPDP resulted in a significant increase in postimplantation loss at 60 µmol/kg, but there was no significant increase in external, visceral, or skeletal abnormalities at any dose. The developmental NOAEL for MnDPDP, therefore, was 40 µmol/kg. These results indicate that the developmental toxicity profile of MnDPDP differs considerably in the rat and rabbit. In the rat, this compound induces specific skeletal abnormalities, whereas in the rabbit, embryo/fetal toxicity is the most sensitive developmental endpoint with no evidence for the induction of specific skeletal abnormalities.


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