title: Serum and tissue pharmacokinetics of silibinin after per os and i.v. administration to mice as a HP-β-CD lyophilized product.
abstract: Silibinin, the main active component of Silybum marianum is a hepatoprotective and antioxidant agent with antitumor effect, exhibiting very low aqueous solubility and oral bioavailability limiting its use in therapeutics. We characterized serum and tissue pharmacokinetics of SLB, calculated its absolute bioavailability and developed an open loop physiologically based pharmacokinetic (PBPK) model, after oral (per os, p.o) and intravenous (i.v.) administration in mice as water-soluble silibinin-hydroxypropyl-beta-cyclodextrin (SLB-HP-β-CD) lyophilized product. 60 C57Bl/6J mice were divided into groups of 5, each group representing one sampling time point. SLB-HP-β-CD lyophilized product was administered orally (50mg/kg) and i.v. (20mg/kg) after reconstitution with water for injection. Blood and tissue samples were collected at selected time points after animal sacrificed, properly treated and analyzed with HPLC-PDA for non-metabolized and total SLB. NONMEM pharmacokinetic analysis revealed a 2-compartment PK model to describe serum SLB pharmacokinetics, with zero order absorption after oral administration and was applied as forcing function to an open loop PBPK model incorporating heart, liver, kidneys and lungs. Tissue/plasma Kp values were estimated using i.v. data and can be used to predict tissue SLB distribution after oral administration. Absolute oral bioavailability of SLB from the lyophilized SLB-HP-β-CD product was 10 times higher than after administration of pure SLB.
authors.affiliation: Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Christodoulou
authors.affiliation: Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
authors.forename: Irene-Ariadne
authors.initials: IA
authors.lastname: Kechagia
authors.affiliation: Laboratory of Analytical Chemistry, Faculty of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
authors.forename: Stavros
authors.initials: S
authors.lastname: Tzimas
authors.affiliation: Department of Experimental Surgery, Bioresearch Foundation of the Academy of Athens, 4 Soranou Efesiou str., 11527 Athens, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Balafas
authors.affiliation: Department of Experimental Surgery, Bioresearch Foundation of the Academy of Athens, 4 Soranou Efesiou str., 11527 Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kostomitsopoulos
authors.affiliation: Laboratory of Analytical Chemistry, Faculty of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Archontaki
authors.affiliation: Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
authors.forename: Aristides
authors.initials: A
authors.lastname: Dokoumetzidis
authors.affiliation: Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece. Electronic address: valsami@pharm.uoa.gr.
authors.forename: Georgia
authors.initials: G
authors.lastname: Valsami
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D005612:Freeze Drying; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D012838:Silymarin; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077385:Silybin
keywords: HP-β-CD; Lyophilization; PBPK model; Serum/tissue pharmacokinetics; Silibinin