title: The influence of the time-of-day administration of sunitinib on the penetration through the blood-brain and blood-aqueous humour barriers in rabbits.
abstract: OBJECTIVE
  Sunitinib is a multiple tyrosine kinase inhibitor (TKI) that exerts anti-tumor and antiangiogenic activity. It is used for the treatment of metastatic gastrointestinal stromal tumours, renal cell carcinoma and pancreatic neuroendocrine tumours. A few studies confirm the anti-tumour activity of sunitinib in brain tumours and uveal melanoma, as well as its efficacy in the reduction of brain metastases of some primary cancers. Therefore, the penetration of sunitinib through the blood-brain barrier (BBB) and blood-aqueous humour barrier (BAB) is an issue of growing interest. The aim of the study was to investigate the influence of the time-of-day administration on the penetration of sunitinib into the cerebrospinal fluid (CSF) and aqueous humour (AH).
  
  
  METHODS
  The rabbits were divided into two groups: I (control group)--receiving sunitinib at 8 a.m., and II--receiving sunitinib at 8 p.m. Sunitinib was administered p.o. at a single dose of 25 mg. The concentrations of sunitinib and its active metabolite (SU12662) in the plasma, CSF, AH were measured with the validated HPLC-UV method.
  
  
  RESULTS
  The plasma AUC0-t for sunitinib in group I was 2051.8 ng × h/mL, whereas in group II it was 3069.3 ng × h/mL. The aqueous humour AUC0-t for sunitinib in thr groups were 43.2 and 76.3 ng × h/mL, respectively. The cerebrospinal AUC0-t for sunitinib in groups I and II were 55.5 and 66.3 ng × h/mL, respectively.
  
  
  CONCLUSIONS
  After the evening administration (8 p.m.) the exposure to sunitinib in the rabbits' plasma, AH and CSF was higher than after the morning administration (8 a.m.), but the degree of sunitinib penetration through the BAB and BBB was very low (< 5%) and comparable in both groups.
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznań, Poland. sobanska.katarzyna@gmail.com.
authors.forename: K
authors.initials: K
authors.lastname: Sobańska
authors.forename: A
authors.initials: A
authors.lastname: Karbownik
authors.forename: E
authors.initials: E
authors.lastname: Szałek
authors.forename: W
authors.initials: W
authors.lastname: Płotek
authors.forename: T
authors.initials: T
authors.lastname: Grabowski
authors.forename: A
authors.initials: A
authors.lastname: Szewczyk
authors.forename: D
authors.initials: D
authors.lastname: Marcinkowska
authors.forename: W
authors.initials: W
authors.lastname: Połom
authors.forename: M
authors.initials: M
authors.lastname: Matuszewski
authors.forename: E
authors.initials: E
authors.lastname: Grześkowiak
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry; D018916:Blood-Aqueous Barrier / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000737:chemistry; D057906:Circadian Clocks / Q000502:physiology; D007211:Indoles / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D011817:Rabbits; D000077210:Sunitinib; D013997:Time Factors
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C544393:SU 12662; D000077210:Sunitinib