Silibinin hemisuccinate binding to proteins in plasma and blood cell/plasma partitioning in mouse, rat, dog and man in vitro.

Background: The determination of plasma protein binding and blood cell/plasma partitioning is important when prescribing silibinin hemisuccinate to patients concomitantly receiving other drugs and to estimate the safety margins of exposure at the no observed adverse events levels determined from toxicity studies conducted in rats and dogs.

Methods: Protein binding of [3'-14C]silibinin hemisuccinate (1, 10, 100, 1000 and 4000 μM) was evaluated in human, dog, rat and mouse plasma by ultrafiltration. Blood cell/plasma partitioning in all these species was also determined.

Results: Silibinin hemisuccinate is highly bound to plasma proteins with percentage binding ranging from 94.3% to 97.8%. Its association with blood cells was negligible (<7%) in all species. The degree of protein binding was concentration independent up to the pharmacologically effective concentration of 100 μM. The blood cell/plasma partitioning indicates that distribution into blood cells is not an important feature for the disposition of silibinin hemisuccinate.

Conclusions: No corrections for fraction unbound are needed when comparing human and preclinical pharmacokinetic and pharmacodynamic data at pharmacological doses, and it is appropriate to analyze plasma as opposed to whole blood for the determination of silibinin hemisuccinate concentrations.