Effective Administration Route for the Deleted Form of Hepatocyte Growth Factor To Exert Its Pharmacological Effects

Abstract

The pharmacokinetics and the pharmacological effects of the deleted form of hepatocyte growth factor (dHGF) after intravenous (iv), subcutaneous (sc), or intramuscular (im) administration (0.25 and 2. 5 mg/kg) were studied in rats. After single iv administration (2.5 mg/kg), dHGF in serum rapidly decreased (alpha- and beta-phase half-life: 3.2 and 26.5 min, respectively). Two to four hours after single sc or im administration (2.5 mg/kg), the serum level of dHGF reached a maximum and then gradually declined (half-life: 2.7 h). The serum levels were not changed by repetitive iv administration, but were dramatically decreased by repetitive sc or im administration. Liver weight and serum levels of total protein, albumin, and HDL-cholesterol were significantly increased by iv administration of dHGF (twice daily for 4 days at 0.25 mg/kg). Sc or im administration of dHGF did not increase these parameters at the same dose, but did significantly at 2.5 mg/kg. These observations suggest that iv administration is the most effective in exerting the pharmacological effects of dHGF among three administration routes. dHGF after iv administration was distributed mainly and rapidly into liver (53.6% of the injected dHGF within 5 min) and was sustained at a higher level in the liver than in plasma. In infusion (0.5 mg/kg/3 h), dHGF level in plasma and liver reached a steady-state 15 and 60 min after starting the infusion, respectively. The steady-state level of dHGF was 7- to 9-fold higher in liver than in plasma, and the higher level in liver was sustained beyond the steady-state.

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

“…36 An additional advantage of using this was that the pharmacokinetics and pharmacological effects of this preparation of dHGF after intravenous injection in rats have been fully described. 37 We confirmed that co-administration of these two growth factors stimulated hepatocyte proliferation more effectively than either growth factor alone and found significant synergy of action between the two growth factors.…”

Gene therapy for preventing neuronal death using hepatocyte growth factor: in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons

“…For example, the alpha-phase of intravenous administration of rHGF was 3.2 min, while the beta-phase was 26.5 min. 30 Similarly, Liu KX et al 31 reported 4 min via intravenous administration. Even intramuscular or subcutaneous injection of rHGF was less than 2.7 h. 31 Thus, the continuous expression of transgene over a long time may be ideal to demonstrate therapeutic effects.…”

“…Recent studies have documented that the subcellular localization of bax determines the fate of cells, as bax protein moves to the mitochondria and other membrane sites, and triggers a catastrophic change of mitochondrial function after delivery of death signals to cells. [30][31][32] Probably, one of the potential mechanisms of how HGF works as an antiapoptotic molecule is to inhibit the translocation of bax, although further studies are necessary.…”

Hepatocyte Growth Factor Protects Functional and Histological Disorders of HgCl₂-Induced Acute Renal Failure Mice

“…Based on previous pharmacokinetic studies, the half-life of HGF is as short as 4 min or less (α phase) and 26.5 min (β phase) in the circulation of rats [22, 23, 24]. This appears to be the reason why HGF administered by intravenous bolus injection gives a transient but very high concentration.…”