title: Stability, pKa and plasma protein binding of roscovitine.
abstract: In the present investigation, the binding of roscovitine (100, 500 and 1500 ng/mL) to plasma proteins was studied at 25 and 37 degrees C by ultrafiltration and equilibrium dialysis methods. Drug stability in plasma was assessed during a 48 h at 4, 25 and 37 degrees C. The effect of thawing and freezing on drug stability was studied. The pKa of roscovitine was measured using capillary electrophoresis coupled with mass spectrometry. Roscovitine was quantified utilizing liquid chromatography and tandem mass spectrometry. Roscovitine is highly bound to plasma proteins (90%). Binding of roscovitine to human serum albumin was constant (about 90%) within concentration range studied while the binding to alpha1-acid glycoprotein decreased with increasing drug concentration indicating that albumin is more important in clinical settings. However, alpha1-acid glycoprotein might be important when plasma proteins change with disease. Protein binding was higher at 25 degrees C compared to 37 degrees C. The results obtained by equilibrium dialysis were in good agreement with those obtained by ultrafiltration. Roscovitine was stable at all temperatures studied during 48 h. Roscovitine has a pKa of 4.4 showing that the drug mainly acts like a weak mono-base. The results obtained in our studies are important prior to clinical trials and to perform pharmacokinetic studies.
authors.affiliation: Department of Medicine, Division of Hematology, Laboratory of Hematology, Karolinska University Hospital, Huddinge S-14186, Sweden. Marina.Vita@medhs.ki.se
authors.forename: Marina
authors.initials: M
authors.lastname: Vita
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Rehim
authors.forename: Christina
authors.initials: C
authors.lastname: Nilsson
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hassan
authors.forename: Patrik
authors.initials: P
authors.lastname: Skansen
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Lennart
authors.initials: L
authors.lastname: Meurling
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
mesh_terms: D001798:Blood Proteins / Q000737:chemistry*; D003956:Dialysis; D004355:Drug Stability; D019075:Electrophoresis, Capillary; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013058:Mass Spectrometry; D009961:Orosomucoid / Q000737:chemistry; D011687:Purines / Q000097:blood / Q000737:chemistry*; D000077546:Roscovitine; D012709:Serum Albumin / Q000737:chemistry; D013696:Temperature; D014462:Ultrafiltration
chemical_list: D001798:Blood Proteins; D009961:Orosomucoid; D011687:Purines; D012709:Serum Albumin; D000077546:Roscovitine