Developmental toxicity of mangafodipir trisodium and manganese chloride in Sprague-Dawley rats.
Mangafodipir trisodium (MnDPDP) is a manganese chelate being developed as a contrast agent for magnetic resonance imaging of the hepatobiliary system. The intended clinical dose is 5 mumol/kg. The potential for MnDPDP to induce embryotoxicity and/or teratogenicity in Sprague-Dawley rats was investigated. Twenty five inseminated rats/group were intravenously administered 0, 2, 5, or 20 mumol/kg MnDPDP from days 6-17 of gestation. Maternal toxicity was not observed at any dose of MnDPDP. There were no treatment-related effects on the numbers of fetuses, fetal viability, numbers of resorptions, implantations and corpora lutea, or the percent of pre- and post-implantation losses. However, at 20 mumol/kg, fetal body weights were significantly decreased (3.3 g vs. 3.9 g for control) and increased skeletal malformations were observed (141/270 vs. 0/285 in control). The malformations were of a specific type, which included angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. To better define the developmental stage that is most susceptible to the effects of MnDPDP, a segmented developmental study was conducted. Twelve inseminated rats were administered 0, 20, 40, or 80 mumol/kg MnDPDP on days 6-8, 9-11, 12-14, or 15-17 of gestation. Skeletal malformations, identical to those seen in the previous study, were increased in a dose-dependent manner with the highest incidence occurring in fetuses from females dosed from days 15-17 of gestation. A third study, in which 15 rats/group were dosed intravenously with 0, 5, 20, or 40 mumol/kg MnCl2 on days 6-17 of gestation, produced identical skeletal malformations to those seen with MnDPDP, indicating that manganese is the active moiety responsible for these specific malformations.
Treinen
K A
KA
Sanofi Research Division, Sanofi Winthrop, Inc., Collegeville, Pennsylvania 19426, USA.
Gray
T J
TJ
Blazak
W F
WF
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities; D002712:Chlorides / Q000008:administration & dosage / Q000633:toxicity*; D003287:Contrast Media / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D005260:Female; D007275:Injections, Intravenous; D017880:Limb Deformities, Congenital; D008297:Male; D017895:Manganese Compounds / Q000008:administration & dosage; D020149:Manganese Poisoning; D009024:Morphogenesis / Q000187:drug effects; D011247:Pregnancy; D011732:Pyridoxal Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity*
D002712:Chlorides; D003287:Contrast Media; D017895:Manganese Compounds; D013723:Teratogens; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid; C025340:manganese chloride