Pharmacokinetics of Crocus sativus L. aqueous extract after peros and intravenous administration to C57/BL6J mice
Ei. Christodoulou(1), Z.I. Kakazanis(2), N. Kostomitsopoulos(2), A. Dokoumetzidis(1), G.Valsami(1)
(1) Laboratory of Biopharmaceutics-Pharmacokinetics, Department of Pharmaceutical Technology, School of Pharmacy, National and Kapodistrian University of Athens, Greece (2) Center of Clinical Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
Objectives: To develop a PK model to describe serum pharmacokinetics and bioavailability of saffron aqueous extract, and especially the PK properties of crocetin, after peros and intravenous administration to mice.
Methods: A lyophilized aqueous extract of Crocus sativus L. stigmata was administered to 80 C57Bl/6J male mice (dose 60 mg/kg body weight) after reconstitution with sterile water. Mice were divided into groups of five and sacrificed at selected time points for blood and tissue sampling. Serum samples were analyzed with an HPLC-DAD method developed for crocetin (the metabolite of crocin, the main antioxidant component of the aqueous extract) [1]. Crocetin serum concentration data after both iv and peros administration were analyzed in NONMEM to describe serum pharmacokinetics and bioavailability of saffron aqueous extract.
Results: Crocetin serum levels were measured after p.o. and i.v. administration of lyophilized saffron aqueous extract using standardized calibration curves. Mean measured Cmax value was found 3±0.18 μg/mL (Tmax=15 min) and 2.7±0.06 μg/mL (Tmax=30 min) for i.v and peros administration respectively. Serum i.v and peros data were described by a one-compartment model parametrized for i.v. administration as V=33.5 mL, CL=55.2 mL/h and ktr=12.1 h‑1 representing the rate of crocin to crocetin transformation (%RE 22.1); and for peros administration V=13.0 mL, CL=41.5 mL/h and ka,tr=2.01 h-1, representing a hybrid rate of absorption and crocin to crocetin transformation (%RE 25.6). Crocetin bioavailability after peros administration was found comparable to i.v. administration of saffron extract, probably because the intestinal tract serves as an important site for crocin (main saffron constituent precursor of crocetin) hydrolysis to crocetin [1] and thereafter rapid absorption and entrance to blood circulation. However, since crocetin is also metabolized to glucuronides, measurement of total crocetin (free+glucuronide) is required and is in process to fully characterize oral bioavailability.
Conclusions: Both i.v. and peros pharmacokinetics of crocetin after single dose administration to C57Bl/6J male mice as saffron extract was adequately described by a one compartment PK model. After p.o. administration crocin, the main constituent of saffron extract, was rapidly hydrolyzed to its active metabolite crocetin in the GI tract and measured serum crocetin levels were comparable to those after i.v. administration.
References:
[1] Xi L, Qian Z, Du P, Fu J. Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats. Phytomedicine 14:633-636, 2007.