Repeated intravenous injection of recombinant human hepatocyte growth factor ameliorates liver cirrhosis but causes albuminuria in rats.
Hepatocyte growth factor (HGF) is a promising agent for the treatment of liver cirrhosis because of its mitogenic and anti-fibrotic effects. We investigated the effect of recombinant human HGF (rh-HGF) on cirrhosis development; its pharmacokinetics and nephrotoxicity in rats with liver cirrhosis induced by 4-week treatment with dimethylnitrosamine (DMN). rh-HGF (0.3 mg/kg) was intravenously administered to rats once a day for 4 weeks in parallel with DMN treatment or twice a day for the last 2 weeks of DMN treatment. Repeated doses of rh-HGF increased the liver weight and serum albumin, and reduced serum ALT. The development of hepatic fibrosis was inhibited more efficiently by extended low-dose treatment with rh-HGF. In cirrhotic rats, serum levels of rh-HGF increased and clearance was decreased, leading to an increase in the area under the plasma-concentration time curve and a decrease in the steady-state volume of distribution. Repeated doses of rh-HGF led to increased urinary albumin excretion, but no rh-HGF-treated animals developed increased serum creatinine levels. Urinary albumin excretion returned to baseline after the cessation of rh-HGF. These results suggest that extended treatment with rh-HGF is required for the attenuation of cirrhosis, and repeated doses of rh-HGF cause adverse effects in extra-hepatic organs. These issues must be resolved before the widespread application of rh-HGF in the treatment of liver cirrhosis.
Kusumoto
Kazunori
K
Department of Internal Medicine II, Faculty of Medicine, University of Miyazaki, Japan.
Ido
Akio
A
Moriuchi
Akihiro
A
Katsura
Toshiya
T
Kim
Ildeok
I
Takahama
Yuka
Y
Numata
Masatsugu
M
Kodama
Mayumi
M
Hasuike
Satoru
S
Nagata
Kenji
K
Uto
Hirofumi
H
Inui
Ken-Ichi
K
Tsubouchi
Hirohito
H
D000410:Alanine Transaminase / Q000097:blood; D000419:Albuminuria / Q000139:chemically induced*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004128:Dimethylnitrosamine; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012709:Serum Albumin
D011994:Recombinant Proteins; D012709:Serum Albumin; D017228:Hepatocyte Growth Factor; D000410:Alanine Transaminase; D004128:Dimethylnitrosamine