Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development.
BACKGROUND
A review of the nonsteroidal anti-inflammatory drug (NSAID) literature suggested occurrences of low-level incidences of cardiovascular and midline defects in rabbit fetuses exposed in utero. Aspirin (acetylsalicylic acid, ASA) is a widely used NSAID that irreversibly inhibits cyclooxygenases (COXs) 1 and 2. ASA has been studied extensively in rats and has consistently increased low-incidence cardiovascular malformations and defects in midline closure. The objectives of the current study were to comprehensively define the developmental toxicology profile of ASA in rabbits by using a dosing paradigm encompassing the period of organogenesis and to test the hypothesis that maternal gastrointestinal toxicity after repeated dose administrations hampers the detection of low-incidence malformations with ASA in rabbits by limiting ASA administration to sensitive windows for cardiovascular development and midline closure.


METHODS
ASA was administered to pregnant New Zealand White rabbits from gestation days (GDs) 7 to 19 at dose levels of 125, 250, and 350 mg/kg per day and as single doses of 500, 750, or 1000 mg/kg on GD 9, 10, or 11. Cesarean sections were performed on GD 29, and the fetuses were examined for external, visceral and skeletal development.


RESULTS
In the repeated dose study, maternal toxicity was exhibited in the 250- and 350-mg/kg per day groups by mortality and decreased food consumption and body weight gain. In the single dose studies, maternal toxicity was exhibited at all doses by reductions in body weight gain and food consumption for 3 days after treatment. Fetal body weight was significantly reduced in the repeated dose study at 350 mg/kg per day. Fetal weights were not affected by single doses of ASA on GD 9, 10, or 11. There were no treatment-related external, visceral or skeletal malformations associated with ASA administration throughout organogenesis or with single doses administered during critical developmental windows.


CONCLUSIONS
These findings supported previous work demonstrating that ASA is not teratogenic in rabbits, as opposed to rats, even when large doses are administered on single days during specific windows of development.
Cappon
G D
GD
Pfizer Global Research & Development, Groton, Connecticut 06340, USA. gregg_d_cappon@groton.pfizer.com
Gupta
U
U
Cook
J C
JC
Tassinari
M S
MS
Hurtt
M E
ME
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity*; D001241:Aspirin / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D018811:Maternal Exposure / Q000009:adverse effects; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D011817:Rabbits; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013723:Teratogens; D001241:Aspirin