title: Silibinin hemisuccinate binding to proteins in plasma and blood cell/plasma partitioning in mouse, rat, dog and man in vitro.
abstract: 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.
authors.affiliation: R&D Division, Rottapharm | Madaus, Via Valosa di Sopra 9, 20900 Monza, Italy. stefano.persiani@rottapharm.com
authors.forename: Stefano
authors.initials: S
authors.lastname: Persiani
authors.forename: Federica
authors.initials: F
authors.lastname: Sala
authors.forename: Richard
authors.initials: R
authors.lastname: Cole
authors.forename: Guy
authors.initials: G
authors.lastname: Webber
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Caselli
authors.forename: Paola
authors.initials: P
authors.lastname: Vaghi
authors.forename: Lucio C
authors.initials: LC
authors.lastname: Rovati
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008297:Male; D051379:Mice; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077385:Silybin; D012838:Silymarin / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; D012838:Silymarin; D000077385:Silybin