Bioavailability Following Oral Administration of a Silibinin-Phosphatidylcholine Complex in Cats
C.B. Webb; B.J. Samber; D. Gustafson; D.C. Twedt
The milk thistle extract silimarin or its active product (silibinin) is shown to have antioxidant effects, one of which is increasing hepatic glutathione concentration. A number of human clinical trials have demonstrated the therapeutic effects of this compound for treating liver disease. Complexing silibinin with phosphatidylcholine (SPC) increases its oral uptake and bioavailability. The bioavailability of SPC was recently demonstrated in dogs but because of the unique characteristics of feline hepatic metabolism the bioavailability may be different. The purpose of this study is to determine the oral bioavailability of a silibinin-phosphatidylcholine complex (SPC) in healthy cats.
Five cats were administered 10 mg/kg of SPC (provided by Nutramax Laboratories) as a powder combined with cornstarch (31% silibinin) in a capsule. Blood samples were drawn prior to SPC administration, and then at the 0.5, 1, 2, 4, 6, 8, and 12 hour time points following SPC administration. Blood samples drawn for silibinin analysis were collected in lithium-heparin tubes, centrifuged, and the plasma stored at -70°C until analyzed. Following a 14 day washout period a single IV dose of silibinin (90.5% pure; 55 mg/cat dissolved in absolute ethanol, resulting in a 50mg silibinin dose per cat) was administered to the same 5 cats. Post-treatment samples were drawn at 5 minutes, 15 minutes, and 0.5, 1, 2, 4, 6, 8, and 12 hour time points. A liquid chromatography-mass spectrometry-mass spectrometry method was used to quantify plasma levels of silibinin. A pharmacokinetic (PK) comparison of IV silibinin versus oral dosing of SPC in cats showed the following: Cmax of 87.1µM ± 44.2 IV and 5.8µM ± 3.1 oral; AUC0inf of 86.6μM·hr ± 81.4 IV and 6.1μM·hr ± 3.5 oral; t1/2λ of 2.51hr ± 1.63 IV and 3.16hr ± 1.74 oral; Vz of 5.65 ± 3.66L IV and 309L ± 165 oral; CL of 1.88L/hr ± 0.99 IV to 74.7L/hr ± 47.1 oral. Comparing these PK parameters for a 10/mg/kg dose of SPC in cats with those of dogs (45 mg/kg) and humans (62 mg/kg) following oral silibinin administration showed the following: Cmax of 5.8µM ± 3.1 in cats, 0.33µM ± 0.25 in dogs, 96.1µM ± 37.3 in humans; AUC04hr of 5.80μM·hr ± 3.46 in cats, 0.69μM·hr ± 0.52 in dogs, 165.1μM·hr ± 66.6 in humans; CL/F of 22.89L/hr ± 14.33 in cats, 11,850L/hr ± 12,187 in dogs, 63.24L/hr ± 27.50 in humans. Oral SPC has a bioavailability of 6-7% in cats. The distinct species differences are best explained by the feline's limited capacity for hepatic glucuronidation of xenobiotics. Oral administration of SPC effectively raised plasma levels of silibinin in these healthy cats. Confirmation of the bioavailability of this complex suggests that oral administration of SPC could be an effective treatment option in with liver disease involving oxidative stress or, depletion of hepatic glutathione concentrations.