Characterization of the inflammatory response to a highly selective PDE4 inhibitor in the rat and the identification of biomarkers that correlate with toxicity.
The primary toxicity associated with repeated oral administration of the PDE4 inhibitor IC542 to the rat is an inflammatory response leading to tissue damage primarily in the gastrointestinal tract and mesentery. Although necrotizing vasculitis is frequently seen with other PDE4 inhibitors, blood vessel injury was rare following IC542 administration and was always associated with inflammation in the surrounding tissue. The incidence and severity of the histologic changes in these studies correlated with elevated peripheral blood leukocytes, serum IL-6, haptoglobin, and fibrinogen, and with decreased serum albumin. By monitoring haptoglobin, fibrinogen and serum albumin changes in IC542-treated rats, it was possible to identify rats with early histologic changes that were reversible. Since PDE4 inhibition is generally associated with anti-inflammatory activity, extensive inflammation in multiple tissues was unexpected with IC542. Co-administration of dexamethasone completely blocked IC542-induced clinical and histologic changes in the rat, confirming the toxicity resulted from inflammatory response. In addition, IC542 augmented release of the proinflammatory cytokine IL-6 in LPS-activated whole blood from rats but not monkeys or humans. The effect of IC542 on IL-6 release from rat leukocytes in vitro is consistent with the proinflammatory response observed in vivo and demonstrates species differences to PDE4 inhibition.
Dietsch
Gregory N
GN
ICOS Corporation, Bothell, Washington 98021, USA. gdietsch@icos.com
Dipalma
Chris R
CR
Eyre
Russell J
RJ
Pham
Tuan Q
TQ
Poole
Karen M
KM
Pefaur
Noah B
NB
Welch
William D
WD
Trueblood
Esther
E
Kerns
William D
WD
Kanaly
Suzanne T
ST
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006242:Haptoglobins / Q000032:analysis; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D008643:Mesentery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013045:Species Specificity; D018675:Toxicity Tests; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015415:Biomarkers; D006242:Haptoglobins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D005340:Fibrinogen