Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine

Medicines

Vamshi K. Manda¹  Bharathi Avula¹  Olivia R. Dale¹  Amar G. Chittiboyina¹  Ikhlas A. Khan¹  Larry A. Walker¹  Shabana I. Khan¹ 

[1] National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; E-Mails:

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

DOI  :  10.3390/medicines2020093

来源: mdpi

【 摘 要 】

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).

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.

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 K_i 19 μM) and non-competitive inhibition of CYP2D6 (IC₅₀ 19 and K_i 26 μM) was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine (30 μM) while lower doses were ineffective.

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.