The influence of sorafenib on hepatic encephalopathy and the mechanistic survey in cirrhotic rats.
BACKGROUND
Sorafenib, a multikinase inhibitor that inhibits angiogenesis and carcinogenesis, has been used for patients with advanced hepatocellular carcinoma. However, sporadic cases have been reported with the development of hepatic encephalopathy (HE) after sorafenib treatment, mostly in those with cirrhosis. Liver function impairment, portal-systemic collaterals and brain oxidative stress participate in the pathogenesis of HE. The study therefore aimed to investigate the potential influences of sorafenib on HE and the relevant risk factors in cirrhotic rats.


METHODS
Liver cirrhosis was induced in Spraque-Dawley rats with common bile duct ligation (CBDL). CBDL rats received sorafenib 1 mg/kg/day or distilled water (DW) via oral gavage since the 15th day post surgery for 2 weeks. On the 28th day, after motor activities measurements, mean arterial pressure, portal pressure and heart rate were checked. Thereafter, cerebral cortex and cerebellum were dissected for oxidative stress study and blood was collected for liver biochemistry survey.


RESULTS
Sorafenib significantly reduced portal pressure (22%) and collateral shunting degree (15%) in cirrhotic rats. Alanine transaminase, aspartate transaminase, total bilirubin and ammonia were similar in sorafenib- and DW-treated groups. Motor activities were not significantly altered by sorafenib. In cerebrum, the oxidant and antioxidant substances activities were not significantly different between the two groups, whereas they were divergent in cerebellum and hippocampus.


CONCLUSIONS
By surveying three main aspects involved in the pathogenesis of HE, this study demonstrates that sorafenib does not increase the risk of HE in cirrhotic rats.
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Shao-Jung
SJ
Hsu
I-Fang
IF
Hsin
Yi-Ling
YL
Lin
Yi-Chen
YC
Chen
Hui-Chun
HC
Huang
Fa-Yauh
FY
Lee
Han-Chieh
HC
Lin
Ching-Chih
CC
Chang
Shou-Dong
SD
Lee
D000818:Animals; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D006801:Humans; D006975:Hypertension, Portal / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib
D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib