Date of Award

5-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

Charles Ryan Yates, Pharm. D., Ph.D.

Committee

Eldon E. Geisert, Ph.D. Leonard Lothstein, Ph.D. Bernd Meibohm, Ph.D. Duane D. Miller, Ph.D.

Abstract

Gliomas, the tumors of glial cells, account for 80% of primary malignant brain tumors. In 2011, there were about 18,300 new cases of maligant gliomas in the United States alone. Patients with glioblastoma multiforme or anaplastic astrocytoma, the two major types of malignant gliomas, have a median survival of 14 months or 2 to 3 years, respectively. Therefore novel treatments for malignant glioma are urgently needed.

A novel series of tetrahydroisoquinoline derivatives with antiglioma activity has been undergoing drug metabolism/pharmacokinetics (DMPK)-guided lead optimization. EDL-291 was result from structure modification of last generation compound EDL-155. Its preclinical pharmacokinetics were characterized in this dissertation project. In male Sprague Daley (SD) rats, after 10 mg/kg intravenous injection, total body clearance (CL) of EDL-291 was 209 mL/min/kg (CV 23.7%), 39% lower than EDL-155 but still much higher than rat liver blood flow. 1.2% of dosed EDL-291 was found in urine (fe) over the 24 hr post-dose period. EDL-291 is stable in whole blood, not accumulated in red blood cells, but susceptible to pulmonary microsomal metabolism. Thus, extensive lung metabolism is the major contributor of the high CL value. The volume of distribution of EDL-291 at steady state (Vdss) in SD rats was 32.5 L/kg (CV 46.6%). The ratio of the EDL-291 brain area under concentration curve (AUC) to plasma AUC between 20 - 180 min after intravenous injection was 14.0. The brain/plasma AUC ratio at 10 - 180 min after 50mg/kg subcutaneous injection to C57BL/6J mice was 4.07. The bioavailability (F) of EDL-291 after 40mg/kg oral gavage in SD rats was 40.4%. Attempts to reduce pulmonary metabolism led to the discovery of EDL-323, which had a dramatically reduced clearance compared to EDL-291. However, the brain penetration of EDL-323 was significantly lower than EDL-291. Thus, further structural modifications are required to achieve both reduced clearance and enhanced brain penetration.

Antigloma activity of EDL compounds was discovered in phenotype screening. A preliminary evaluation of the effect of EDL-291 on human glioma cell apoptosis machinery was conducted as part of the effort to elucidate its mechanism of action. After EDL-291 treatment, active caspase-3 and the amount of cleaved PARP were increased in both U87MG and U-251 cells. In addition, the antiproliferative effect of EDL-291 was partially reversed by a caspase-3/7 inhibitor. However, neither the caspase-8 inhibitor nor caspase-9 inhibitor reversed the apoptotic effect of EDL-291. Decylubiquinone (dUb) can enhance caspase-3 activation as well as antiproliferative effect caused by EDL-291 treatment. Therefore, dUb could be a candidate companion drug of EDL-291 analogs in treating glioma.

DOI

10.21007/etd.cghs.2012.0191

Comments

Two year embargo expired May 2014

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