title: Plasma and cerebrospinal fluid pharmacokinetics of the novel tetrahydroisoquinoline EDL-155 in rats.
abstract: OBJECTIVE
  Tetrahydroisoquinolines (THIs) have demonstrated anti-cancer activity in rodent models of glioma, a form of brain cancer refractory to therapeutic intervention. In this study, peripheral and cerebrospinal fluid (CSF) pharmacokinetics in rats were determined to assess the drug developability of the novel THI EDL-155 for the treatment of glioma.
  
  
  METHODS
  Serial blood and CSF samples were collected from rats following intravenous bolus administration of EDL-155 (10-20 mg/kg). Samples were analyzed by LC/MS/MS. Pharmacokinetic analyses using compartmental and noncompartmental methods were performed using the computer program WinNonlin. Plasma protein binding was measured using the charcoal adsorption method. The in vivo efficacy of EDL-155 (i.p. 20 mg/kg twice daily for 7 days) was assessed in rats with stereotactically implanted C6 glioma cells into the caudate.
  
  
  RESULTS
  EDL-155 plasma concentration data were described by a one-compartment model. EDL-155 demonstrated rapid clearance (342.5+/-49.9 ml/min/kg), high volume of distribution (13.0+/-1.2 l/kg) and a terminal half-life of 23.7+/-1.5 min. Dose-normalized CSF area under the curve (AUC(CSF)) as a percentage of peripheral exposure (AUC(Plasma)) was 1.4%. EDL-155 was highly bound to plasma proteins (>93%). Intracranial tumor volume at 7 days post-implantation was approximately 30% smaller in animals treated with EDL-155 when compared to vehicle control animals (13.2+/-5.3 mm(3) vs. 18.7+/-6.3 mm(3); P=0.04).
  
  
  CONCLUSIONS
  High clearance and extensive protein binding limit the brain availability of EDL-155 following systemic administration. EDL-155 treatment resulted in reduced tumor size despite limited blood brain barrier penetrability, which suggests that analogs with increased metabolic stability and brain penetrability may provide a therapeutic option for primary central nervous system tumors such as glioma. On-going studies are focused on the design, synthesis, and testing of novel analogs based upon these findings.
authors.affiliation: Department of Preclinical Development and Clinical Pharmacology, ArQule, Inc., Woburn, MA, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Song
authors.forename: Fei
authors.initials: F
authors.lastname: Ma
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: XiangDi
authors.initials: X
authors.lastname: Wang
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.forename: Suma
authors.initials: S
authors.lastname: Ramagiri
authors.forename: William E
authors.initials: WE
authors.lastname: Orr
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Eldon
authors.initials: E
authors.lastname: Geisert
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yates
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001682:Biological Availability; D001932:Brain Neoplasms / Q000378:metabolism; D002853:Chromatography, Liquid; D005910:Glioma / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; C529597:EDL-155; D044005:Tetrahydroisoquinolines