Plasma and cerebrospinal fluid pharmacokinetics of the novel tetrahydroisoquinoline EDL-155 in rats

Pengfei Song, Fei Ma, Fan Wang, Xiangdi Wang, Renukadevi Patil, Suma Ramagiri, William E. Orr, Duane Miller, Eldon Geisert, Charles Yates

Research output: Contribution to journalArticle

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Abstract

Purpose: 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 (AUCCSF) as a percentage of peripheral exposure (AUCPlasma) 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 mm3 vs. 18.7 ± 6.3 mm3; P = 0.04). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1037-1044
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume61
Issue number6
DOIs
StatePublished - May 1 2008

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Tetrahydroisoquinolines
Cerebrospinal fluid
Pharmacokinetics
Cerebrospinal Fluid
Rats
Plasmas
Glioma
Tumors
Brain
Protein Binding
Blood Proteins
Animals
EDL-155
Central Nervous System Neoplasms
Charcoal
Neurology
Therapeutics
Tumor Burden
Blood-Brain Barrier
Brain Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Plasma and cerebrospinal fluid pharmacokinetics of the novel tetrahydroisoquinoline EDL-155 in rats. / Song, Pengfei; Ma, Fei; Wang, Fan; Wang, Xiangdi; Patil, Renukadevi; Ramagiri, Suma; Orr, William E.; Miller, Duane; Geisert, Eldon; Yates, Charles.

In: Cancer Chemotherapy and Pharmacology, Vol. 61, No. 6, 01.05.2008, p. 1037-1044.

Research output: Contribution to journalArticle

Song, Pengfei ; Ma, Fei ; Wang, Fan ; Wang, Xiangdi ; Patil, Renukadevi ; Ramagiri, Suma ; Orr, William E. ; Miller, Duane ; Geisert, Eldon ; Yates, Charles. / Plasma and cerebrospinal fluid pharmacokinetics of the novel tetrahydroisoquinoline EDL-155 in rats. In: Cancer Chemotherapy and Pharmacology. 2008 ; Vol. 61, No. 6. pp. 1037-1044.
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abstract = "Purpose: 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 (AUCCSF) as a percentage of peripheral exposure (AUCPlasma) 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 mm3 vs. 18.7 ± 6.3 mm3; P = 0.04). Conclusion: 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.",
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T1 - Plasma and cerebrospinal fluid pharmacokinetics of the novel tetrahydroisoquinoline EDL-155 in rats

AU - Song, Pengfei

AU - Ma, Fei

AU - Wang, Fan

AU - Wang, Xiangdi

AU - Patil, Renukadevi

AU - Ramagiri, Suma

AU - Orr, William E.

AU - Miller, Duane

AU - Geisert, Eldon

AU - Yates, Charles

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Y1 - 2008/5/1

N2 - Purpose: 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 (AUCCSF) as a percentage of peripheral exposure (AUCPlasma) 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 mm3 vs. 18.7 ± 6.3 mm3; P = 0.04). Conclusion: 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.

AB - Purpose: 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 (AUCCSF) as a percentage of peripheral exposure (AUCPlasma) 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 mm3 vs. 18.7 ± 6.3 mm3; P = 0.04). Conclusion: 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.

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