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1

National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA

2

Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA

3

Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 12372, Saudi Arabia





*

Author to whom correspondence should be addressed.



Academic Editor: Il-Moo Chang

Abstract Background: Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in the literature. Due to increasing use of dietary supplements in combination with conventional drugs, the risk of adverse effects is on the rise. As a preliminary step to predict a possibility of drug interaction during concomitant use of vinpocetine and conventional drugs, this study was carried out to evaluate the effects of vinpocetine on three main regulators of pharmacokinetic drug interactions namely, cytochromes P450 CYPs, P-glycoprotein P-gp, and Pregnane X receptor PXR. Methods: Inhibition of CYPs was evaluated by employing recombinant enzymes. The inhibition of P-gp was determined by calcein-AM uptake method in transfected and wild type MDCKII cells. Modulation of PXR activity was monitored through a reporter gene assay in HepG2 cells. Results: Vinpocetine showed a strong inhibition of P-gp EC50 8 µM and a moderate inhibition of recombinant CYP3A4 and CYP2D6 IC50 2.8 and 6.5 µM with no activity towards CYP2C9, CYP2C19 and CYP1A2 enzymes. In HLM, competitive inhibition of CYP3A4 IC50 54 and Ki 19 µM and non-competitive inhibition of CYP2D6 IC50 19 and Ki 26 µM was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine 30 µM while lower doses were ineffective. Conclusion: Strong inhibition of P-gp by vinpocetine is indicative of a possibility of drug interactions by altering the pharmacokinetics of drugs, which are the substrates of P-gp. However, the effects on CYPs and PXR indicate that vinpocetine may not affect CYP-mediated metabolism of drugs, as the inhibitory concentrations are much greater than the expected plasma concentrations in humans. View Full-Text

Keywords: vinpocetine; vincamine; pharmacokinetic drug interactions; PXR; CYP450 enzymes; P-gp vinpocetine; vincamine; pharmacokinetic drug interactions; PXR; CYP450 enzymes; P-gp





Autor: Vamshi K. Manda 1, Bharathi Avula 1, Olivia R. Dale 1, Amar G. Chittiboyina 1, Ikhlas A. Khan 1,2,3, Larry A. Walker 1,2 and Shabana I. Khan 1,2,3,*

Fuente: http://mdpi.com/



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