Population Pharmacokinetic Analysis of Silymarin Bioavailability in Rats
I. Locatelli (1), B. Perissutti (2), D Voinovich (2), A. Mrhar (1), I. Grabnar (1)
(1)Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia; (2)Department of Pharmaceutical Sciences, University of Trieste, Trieste, Italy
Objectives: Silymarin, an extract of the seeds of Silybum marianum L. (milk thistle), is used for treatment of liver diseases. It contains several active flavonolignans; the major are silybin, which is a mixture of diastereomers A and B, and silychristin [1]. Low bioavailability of silybin and silychristin is related to low solubility of dry extracts. In order to enhance the solubility, S. marianum dry extract was coground with two polymers: crospovidone (PVP-CL) and carboxymethylcellulose (Ac-Di-Sol) [2]. In this study population PK analysis was used to investigate the relative bioavailability of silybin A, silybin B, and silychristin for the coground systems.
Methods: A new HPLC-UV method was developed for quantification of the three components of interest [2]. The amount of silybin A, silybin B, and silychristin in S. marianum dry extract was 17, 16, and 21%, respectively. Two dose levels of the dry extract (50 and 100 mg/kg), one dose level for Ac-Di-Sol coground system (50 mg/kg) and three dose levels for PVP-CL coground system (50, 100, and 200 mg/kg) were administered to rats. Single blood samples per animal were drawn at 0.5, 1, 2, and 4 h post dose. The plasma concentrations were modeled separately for each of the compounds measured. BLQ levels were replaced with LLOQ/2 values. The base model was a one compartment model with first order absorption and interanimal variability on CL/F and V/F. Residual error was fixed to the highest variability of the assay for the quantified concentrations and to 25% for the BLQ levels [3]. FOCE with interaction was used for parameter estimation in NONMEM.
Results: Bioavalability for Ac-Di-Sol coground system compared to the dry extract was 20, 6.2, and 7.1 times higher for silybin A, silybin B and silychristin, respectively. Comparing PVC-CL coground system to the dry extract, 5.9 and 3.2 times higher bioavailability was noted for silybin A and silybin B, respectively, while for the silychristin it was lower (0.76). Additionally, for silybin A and silybin B bioavailability decreased with dose.
Conclusions: The bioavalilability of silymarin components was substantionally improved in Ac-Di-Sol coground system. However, lower bioavailability can be expected with higher doses.
References:
[1] Dixit N, Baboota S, Kohli K, et al. Silymarin: A review of pharmacological aspects and bioavailability enhacement approaches. Indian J Pharmacol 2007 39(4) 172-9.
[2] Voinovich D, Perissutti B, Magarotto L, et al. Solid state mechanochemical simultaneous activation of the constituents of the Silybum marianum phytocomplex with crosslinked polymers. J Pharm Sci 2009 98(1) 215-28.
[3] Hing JP, Woolfrey SG, Greenslade D, et al. Analysis of toxicokinetic data using NONMEM: impact of quantification limit and replacement strategies for censored data. J Pharmacokinet Pharmacodyn 2001 28(5) 465-79.
