Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine.

Vamshi Manda,Bharathi Avula,Larry Walker,Olivia Dale,Shabana Khan,Amar Chittiboyina,Ikhlas Khan

doi:10.3390/medicines2020093

Vamshi Manda, Bharathi Avula + Show 5 more

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https://doi.org/10.3390/medicines2020093

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Journal: Medicines	Publication Date: Jun 5, 2015
Citations: 37	License type: CC BY 4.0

Affiliation: University of Mississippi, King Saud University

Abstract

BackgroundVinpocetine, 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).MethodsInhibition 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.ResultsVinpocetine 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.ConclusionStrong 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.

Highlights

Vinpocetine is a semi-synthetic derivative of a natural alkaloid vincamine, present in the leaves ofVinca minor plant
Food and Drug Administration (FDA) has recommended preliminary in vitro studies to identify compounds that may have potential to cause drug interactions. These studies are primarily focused on evaluating the modulatory effects of an investigational compound/drug on Cytochromes P450 (CYP), P-gp or Pregnane X receptor (PXR) [23]
Based on the recombinant CYP inhibition results, we further evaluated the inhibitory activity of vinpocetine on CYP3A4 and CYP2D6 in human liver microsomes (HLM) using testosterone and dextromethorphan as probe substrates

Summary

Introduction

It is known as ethyl apovincaminate (Figure 1). In the US, and all other countries, it is sold as a dietary supplement and is a component of many products with muscle building and weight-loss claims. It is primarily marketed as a neuroprotective and memory-enhancing supplement. Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. 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

Results

Conclusion