The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats.
BACKGROUND
Blocking of EGFR signaling by the tyrosine kinase inhibitor AEE788 was well tolerated and did not inhibit liver regeneration after standard 70% partial hepatectomy (PH) in a rat model, as demonstrated previously. However, serum levels of AEE788 at POW1 were 3-fold higher than in the non-resected control group. Therefore, we expanded theses studies to a model of extended 90%PH to investigate the role of liver size for the metabolism of AEE788 and its potential influence on side effects, liver regeneration and liver remodeling.


METHODS
Rats treated with 50 mg/kg AEE788 or solvent every other day orally were subjected to 90%PH. Animals were sacrificed at 1, 2, 7 and 28 days after PH. We measured plasma and liver levels of AEE788 and assessed anti-proliferative side effects, liver regeneration, and liver architecture.


RESULTS
Liver regeneration and liver architecture were not impaired by AEE788 treatment after 90%PH. 90%PH caused a clinically relevant drug accumulation within 1 week of treatment (AEE788 serum and tissue levels: 90%PH*>70%PH*>normal control, *p < 0.05), suggesting a liver-size-dependent metabolism of the drug. Drug accumulation after 90%PH was associated with severe side effects (delayed body weight recovery, diarrhea, impaired hair growth) within 1 week of treatment.


CONCLUSIONS
Treatment with AEE788 could be a potential strategy for adjuvant treatment after oncological liver resection, as liver regeneration was not impaired. Our results suggest a liver-size-dependent metabolism of AEE788 leading to drug accumulation and subsequently to severe side effects. It calls for therapeutic drug monitoring in the early postoperative phase after extended resection.
Deng
Meihong
M
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
Huang
Hai
H
Jin
Hao
H
Dirsch
Olaf
O
Dahmen
Uta
U
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006439:Hemodynamics / Q000187:drug effects; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011182:Postoperative Care; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016622:Silver Staining; D014841:von Willebrand Factor / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011687:Purines; D014841:von Willebrand Factor; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788