Ei.Christodoulou (1), I.A.Kechagia (1), N.Kostomitsopoulos (2), E.Balafas (2), E.Archontaki (3), A.Dokoumetzidis (1), G.Valsami (1)
(1) Faculty of Pharmacy, National and Kapodistrian University of Athens, (2) Center for Experimental Surgery, Biomedical Research Foundation of the Academy of Athens, (3) Faculty of Chemistry, National and Kapodistrian University of Athens
Objectives: To characterize tissue[1] pharmacokinetics (PK) of the water insoluble hepatoprotective flavonoid silibinin (SLB), after peros and intravenous (i.v.) administration as a water soluble lyophilized product with hydroxypropyl-beta-cyclodextrin (HP-β-CD) to mice and develop open loop PBPK tissue models.
Methods: A lyophilized SLB-HP-β-CD product was administered orally (50mg/kg) and i.v. (20mg/kg) to 60 C57bl/6J male mice after reconstitution with water for injection. Mice were divided into groups of five and were sacrificed at selected time points for blood and tissue (liver, brain, kidneys, heart, lungs and spleen) sampling. Serum and homogenized tissue samples were analyzed with an HPLC method developed for SLB. Parent SLB (non-metabolized) and total SLB (metabolized plus non-metabolized, calculated after sample incubation with the enzyme β-glucuronidase) were determined. Empirical PK models were fitted to the i.v. serum data for parent SLB. The model describing the serum concentration was used as forcing function for open loop PBPK[2,3] tissue models. Perfusion and permeability limited tissue models were assessed and model selection was based on basic goodness of fit plots and the Akaike criterion. Peros serum data were analyzed in a similar manner, using NONMEM.
Results: SLB is rapidly and extensively absorbed from GI tract after peros administration of the lyophilized SLB-HP-β-CD product and highly distributed in liver, kidneys, heart and lungs after both peros and i.v. administration accomplishing relatively high levels in tissue homogenates. No SLB levels were detected in brain tissues, and spleen was unable to be homogenized and furthermore analyzed. Serum data were described by a bicompartmental model, parametrized as CL (3.34 ml/h/gr), V1 (1.37 ml/gr), Q (2.47 ml/h/gr) and V2 (44.3 ml/gr). Perfusion limited PBPK tissue models were used for heart, kidneys and liver and the estimated Kp values were 0.35, 2.62 and 4.31, respectively. Data from the lungs could not be analyzed. Similar results were obtained from the peros data. The absolute oral bioavailability of parent and total SLB after administration as a lyophilized SLB-HP-β-CD product was 20% and 45.5%, respectively.
Conclusions: Rapid and extensive absorption of SLB after peros administration of the lyophilized silibinin-HP-β-CD product and extensive distribution to liver, kidneys, heart and lungs is observed. The developed PBPK model can adequately predict the concentration in liver, the main target of SLB.
References:
[1]J. Zhao and R. Agarwal. Tissue distribution of silibinin the major active constituent of sylimarin in mice and its association with enhancement of phase II enzymes: implication in cancer chemoprevention.Carcinogenesis, 20:2101-2108, 1999
[2]I. Nestorov. Whole Body Pharmacokinetic Models. Clin Pharmacokinet, 42 (10): 883-908, 2003
[3]I. Nestorov. Whole Body-Physiologically based pharmacokinetic models. Expert Opin Drug Metab Toxicol, 3(2):235-49, 2007
Reference: PAGE 23 () Abstr 3107 [www.page-meeting.org/?abstract=3107]
Poster: Drug/Disease modeling - Absorption & PBPK