Pharmacokinetic Modeling of Hepatocyte Growth Factor in Experimental Animals and Humans

Abstract

Running title:Pharmacokinetic model of HGF after single and repeated dosesThe second and third authors contributed equally to this work.

Pharmacokinetics and Pharmacodynamics following Intravenous Administration of Recombinant Human Hepatocyte Growth Factor in Rats with Renal Injury

“…We have previously indicated that the basic pharmacokinetic profiles and parameters obtained from experimental animal species (mouse, rat and monkey) could be extrapolated to those in humans [29]. Our present results indicate that the pharmacokinetic profiles of HGF in patients with kidney diseases may be stable, perhaps regardless of the severity of the kidney injury.…”

“…A previous pharmacokinetic analysis indicated that the plasma HGF levels tend to decrease rapidly and that HGF is primarily accumulated in the liver [13,14]. When HGF was administered intravenously, plasma HGF decreased in 2 distinct phases [29]. The α-phase (the 1st phase) that corresponds to the steep decrease in plasma HGF within 30 min is attributable to an association of HGF with capillary vessels and cell surface binding sites [12,29].…”

“…Following the functional association of HGF to Met, cell-surface Met disappears through endocytosis/internalization [15,26]. For these reasons, liver injury affects the clearance profile of the β-phase; plasma clearance of HGF was decreased in rats with acute liver injury [12], but not in mice with AKI [29], and a decrease in the plasma clearance of HGF in rats with liver injury was associated with prolonged plasma HGF levels [15]. In the present study, because the liver injury was mild in glycerol-induced AKI or undetectable in ischemia-reperfusion-induced AKI, minimal change in the pharmacokinetic profiles of recombinant HGF in the plasma was noted between normal rats and rats with acute or chronic kidney injury.…”

“…When HGF was administered intravenously, plasma HGF decreased in 2 distinct phases [29]. The α-phase (the 1st phase) that corresponds to the steep decrease in plasma HGF within 30 min is attributable to an association of HGF with capillary vessels and cell surface binding sites [12,29]. The β-phase (the 2nd phase) shows a slower decay that is attributable to clearance that is mediated by Met and by sulfated proteoglycans in the liver [30].…”

Hepatocyte growth factor and alternative splice variants - expression, regulation and implications in osteogenesis and bone health and repair

“…Despite these findings in animals, HGF has not yet been found effective in the therapeutic treatment of chronic fibrotic diseases in humans 7 . However, HGF is being investigated as a possible treatment for renal failure due to its role as a mitogenic and motogenic factor, which may help stimulate kidney regeneration 70 . Studies in a mouse model of Duchenne muscular dystrophy demonstrated that HGF is being suppressed by NF-κB signaling, and that knock-out of the NF-κB gene, or use of NF-κB chemical inhibitors leads to an increase in HGF transcription and skeletal HGF levels stimulating HGF-induced muscle repair 55 .…”