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Journal of Toxicology
Volume 2012 (2012), Article ID 308594, 7 pages
http://dx.doi.org/10.1155/2012/308594
Research Article

Phospholipogenic Pharmaceuticals Are Associated with a Higher Incidence of Histological Findings than Nonphospholipogenic Pharmaceuticals in Preclinical Toxicology Studies

1Biologics Research, Janssen Research and Development, LLC, 145 King of Prussia Road, Radnor, PA 19087, USA
2Safety Assessment, AstraZeneca Pharmaceuticals, Pepparedsleden 1, 431 83 Mölndal, Sweden
3Haskell Global Centers for Health and Environmental Sciences, DuPont Central Research and Development, Newark, DE 19711, USA
4Safety Assessment, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA 02451, USA

Received 15 March 2012; Accepted 10 April 2012

Academic Editor: J. J. Stegeman

Copyright © 2012 Linda R. Barone et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics.