Comparison of developmental toxicology of aspirin (acetylsalicylic acid) in rats using selected dosing paradigms.
BACKGROUND
Analysis of the literature for nonsteroidal anti-inflammatory drugs (NSAIDs) suggests that a low incidence of developmental anomalies occurs in rats given NSAIDs on specific days during organogenesis. Aspirin (acetylsalicylic acid [ASA]), an irreversible cyclooxygenase 1 and 2 inhibitor, induces developmental anomalies when administered to Wistar rats on gestational day (GD) 9, 10, or 11 (Kimmel CA, Wilson JG, Schumacher HJ. Teratology 4:15-24, 1971). There are no published ASA studies using the multiple dosing paradigm of GDs 6 to 17. Objectives of the current study were to compare results between Sprague-Dawley (SD) and Wistar strains when ASA is administered on GD 9, 10, or 11; to compare the malformation patterns following single and multiple dosings during organogenesis in SD rats; and to test the hypothesis that maternal gastrointestinal toxicity confounds the detection of low incidence malformations with ASA when a multiple dosing paradigm is used.


METHODS
ASA was administered as a single dose on GD 9 (0, 250, 500, or 625 mg/kg), 10 (0, 500, 625, or 750 mg/kg), or 11 (0, 500, 750, or 1000 mg/kg) and from GD 6 to GD 17 (0, 50, 125, or 250 mg/kg a day) in the multiple dose study to SD rats. Animals were killed on GD 21, and fetuses were examined viscerally.


RESULTS
The literature evaluation suggested that NSAIDs induce ventricular septal defects (VSDs) and midline defects (MDs) in rats and diaphragmatic hernia (DH), MDs, and VSDs in rabbits (Cook JC et al., 2003); hence, the present study focused on these malformations, even though ASA induces several other low-incidence malformations. In single dose studies, DH, MD, and VSD were induced on GDs 9 and 10. VSD also was noted following treatment on GD 11. In contrast, DH and MD were noted in the multiple dose study design only in the high-dose group, and VSD was noted across all dose groups.


CONCLUSIONS
High concordance in major developmental anomalies between Wistar and SD rats were noted with the exception of VSD in the SD rats and hydrocephalus in the Wistar rats. Variations and malformations were similar when ASA was administered as a single dose or during the period of organogenesis (GDs 6 to 17). It was also evident that, by titrating the dose to achieve a maximum tolerated dose, malformations that normally occur at low incidence, as reported from previous single dose studies, could also be induced with ASA given at multiple doses.
Gupta
Utpal
U
Drug Safety Evaluation, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. utpal_gupta@groton.pfizer.com
Cook
Jon C
JC
Tassinari
Melissa S
MS
Hurtt
Mark 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; D005865:Gestational Age; D006345:Heart Septal Defects, Ventricular / Q000139:chemically induced; D006548:Hernia, Diaphragmatic / Q000139:chemically induced; D018811:Maternal Exposure / Q000009:adverse effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D013723:Teratogens / Q000633:toxicity*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013723:Teratogens; D001241:Aspirin