title: Pharmacokinetic modeling of hepatocyte growth factor in experimental animals and humans.
abstract: Hepatocyte growth factor (HGF) is under development for treatment of renal failure. This study was designed to clarify changes in HGF pharmacokinetics in renal failure and to establish a pharmacokinetic model applicable to single and repeated doses. The plasma concentration profile in mice with glycerol-induced acute renal failure was similar to that in normal mice, indicating a minimal contribution of kidney to systemic clearance of HGF. Nevertheless, accumulation of fluorescein-4-isocyanate-labeled HGF in renal tubules in both cases suggests the occurrence of efficient endocytosis of HGF in kidney. A pharmacokinetic model including plasma and liver compartments was constructed, incorporating both high- and low-affinity receptors for association and subsequent endocytosis of HGF because HGF is eliminated via specific receptor c-Met and heparin-like substance. The model well explained the plasma concentration profiles at all doses examined after bolus injection in animals and humans, and those during infusion in rodents. It includes externalization of receptors, which is negatively regulated by HGF, and can explain the gradual increase in trough concentration during repeated dosing in monkeys. Overall pharmacokinetic profiles of HGF are governed by at least two receptors and are well described by this pharmacokinetic model, which should assist in safe management of clinical trials.
authors.affiliation: Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Saki
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kazusa
authors.initials: K
authors.lastname: Sano
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Abe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Fukuta
authors.forename: Kiichi
authors.initials: K
authors.lastname: Adachi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000208:Acute Disease; D000818:Animals; D019540:Area Under Curve; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004705:Endocytosis; D005990:Glycerol; D000882:Haplorhini; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D008954:Models, Biological; D017711:Nonlinear Dynamics; D019859:Proto-Oncogene Proteins c-met; D051381:Rats; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D012076:Renal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C066855:HGF protein, human; D011994:Recombinant Proteins; D012076:Renal Agents; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D005990:Glycerol