Tamer E Fandy1, Inas Abdallah2,3, Maan Khayat4, David A Colby5, Hazem E Hassan6,7. 1. Department of Pharmaceutical Sciences, Albany College of Pharmacy, Colchester, VT, USA. 2. Pharmacokinetics and Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N Pine Street, Room: N525 (Office), Baltimore, MD, 21201, USA. 3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Cairo, Egypt. 4. Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah, KSA. 5. Department of BioMolecular Science, University of Mississippi, University, MS, USA. 6. Pharmacokinetics and Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N Pine Street, Room: N525 (Office), Baltimore, MD, 21201, USA. hhassan@rx.umaryland.edu. 7. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo, Egypt. hhassan@rx.umaryland.edu.
Abstract
PURPOSE: Vincamine, vinpocetine and eburnamonine are alkaloids known for their neuroprotective attributes, enhancement of cerebrovascular blood flow and antitumor effect of their derivatives. However, the relative metabolic stability of these alkaloids and their extrusion by the drug efflux transporters expressed at the blood-brain barrier (BBB) are not clear. In this study, we developed rapid and sensitive methods for the detection of these alkaloids and investigated their relative metabolic stability and their interaction with drug efflux transporters. METHODS: UPLC methods were developed to analyze metabolic in vitro samples. Intrinsic clearance was determined using rat liver microsomal enzymes. Drug-stimulated transporter activity was estimated by measuring inorganic phosphate released from ATP spectrophotometrically. RESULTS: The UPLC methods quantification level ranged from 0.02 to 0.025 µg/mL, indicating high sensitivity. The intrinsic clearance of eburnamonine was significantly less than both vincamine and vinpocetine. Different concentrations of the three drugs (4, 20 and 100 µM) induced minimal stimulation of the ATPase activity of the Bcrp and Pgp membrane transporters. CONCLUSIONS: The developed simple, sensitive and reliable UPLC analysis methods can be utilized in future in vitro and in vivo studies. The three alkaloids demonstrated minimal interaction with the drug efflux transporters Pgp and Bcrp, concordant with the ability of these alkaloids to cross the BBB. The relative metabolic stability of eburnamonine compared to the other alkaloids suggests the use of eburnamonine or its derivatives as lead compounds for the development of antitumor and nootropic agents that need to cross the BBB and produce their pharmacological effects in the CNS.
PURPOSE:Vincamine, vinpocetine and eburnamonine are alkaloids known for their neuroprotective attributes, enhancement of cerebrovascular blood flow and antitumor effect of their derivatives. However, the relative metabolic stability of these alkaloids and their extrusion by the drug efflux transporters expressed at the blood-brain barrier (BBB) are not clear. In this study, we developed rapid and sensitive methods for the detection of these alkaloids and investigated their relative metabolic stability and their interaction with drug efflux transporters. METHODS: UPLC methods were developed to analyze metabolic in vitro samples. Intrinsic clearance was determined using rat liver microsomal enzymes. Drug-stimulated transporter activity was estimated by measuring inorganic phosphate released from ATP spectrophotometrically. RESULTS: The UPLC methods quantification level ranged from 0.02 to 0.025 µg/mL, indicating high sensitivity. The intrinsic clearance of eburnamonine was significantly less than both vincamine and vinpocetine. Different concentrations of the three drugs (4, 20 and 100 µM) induced minimal stimulation of the ATPase activity of the Bcrp and Pgp membrane transporters. CONCLUSIONS: The developed simple, sensitive and reliable UPLC analysis methods can be utilized in future in vitro and in vivo studies. The three alkaloids demonstrated minimal interaction with the drug efflux transporters Pgp and Bcrp, concordant with the ability of these alkaloids to cross the BBB. The relative metabolic stability of eburnamonine compared to the other alkaloids suggests the use of eburnamonine or its derivatives as lead compounds for the development of antitumor and nootropic agents that need to cross the BBB and produce their pharmacological effects in the CNS.
Entities:
Keywords:
Alkaloids; Blood–brain barrier; Drug efflux transporters; Rat liver microsomes
Authors: Dilini C Gunasekara; Mary M Zheng; Tara Mojtahed; James R Woods; Tamer E Fandy; Mark V Riofski; Carlotta A Glackin; Hazem E Hassan; Julia Kirshner; David A Colby Journal: ChemMedChem Date: 2016-09-28 Impact factor: 3.466
Authors: Muhammad Ayaz Mustufa; Cigdem Ozen; Imran Ali Hashmi; Afshan Aslam; Jameel Ahmed Baig; Gokhan Yildiz; Shoaib Muhammad; Imam Bakhsh Solangi; Naim Ul Hasan Naqvi; Mehmet Ozturk; Firdous Imran Ali Journal: BMC Cancer Date: 2016-11-14 Impact factor: 4.430