Effect of resveratrol on dipeptidyl peptidase-4 inhibitors pharmacokinetics: An in vitro and in vivo approach
Graphical abstract
Introduction
Diabetes mellitus (DM) is a metabolic disorder. It is primarily associated with decreased insulin secretion by beta cells of the pancreas leading to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors are extensively used as antihyperglycemic agents in type 2 DM patients. DPP-4 enzyme breaks-down glucose-dependent insulinotropic polypeptide (GIP) and incretin. Insulin secretion is stimulated from beta cells by the elevated levels of incretin. This in turn leads to its anti-hyperglycemic effect [1]. The long term hyperglycemia in DM patients leads to dysfunction, and failure of organs.
Vital processes such as cell signaling, aging degenerative diseases and normal oxygen metabolism yield oxidant species as their products [2]. In a healthy state, an intricate balance exists between oxidant species [3] and anti-oxidant activity to prevent potential damage due to excess oxidant species. Factors that lead to an imbalance between the oxidant species or antioxidant equilibrium may lead to excess oxidative stress and subsequent tissue injury [2].
Oxidative stress is a substantial contributor to the damage caused in DM [4]. There is an increase in the level of oxidant species generation in patients with DM [5,6]. Numerous pathophysiological mechanisms underlying diabetic nephropathy and neuropathy have been defined in which increased oxidant species have been recognized as the single amalgamating upstream event [7,8]. Diabetic nephropathy is a complication of DM related to kidneys also called diabetic kidney disease. It is one of the foremost causes of chronic kidney disease and end-stage renal disease, which is a progressive and irreversible kidney disease. Approximately 40% of patients with DM ultimately develop kidney disease. This increases the mortality rates associated with DM [[9], [10], [11]]. Diabetic neuropathy is another complication where there is damage to the nerve due to DM. About 50–60% of patients with diabetes suffer from diabetic neuropathy and it is one of the most frequent sources of autonomic failure and non-traumatic amputation. Complex changes in functional and sensorimotor parameters are the distinguishing features of diabetic neuropathy in patients with DM.
Several plants produce a stilbenoid, natural polyphenol and phytoalexin called resveratrol (RES) in response to injury or when attacked by pathogens. RES is a phytochemical naturally present in grapes, peanuts and berry [12]. Red wine has the highest concentration of RES compared to grapefruit juice and RES supplements are available in the market. RES has numerous pharmacological activities for clinical use like anti-oxidative, antiaging, cardioprotective, neuroprotective, anti-inflammatory and anti-cancer activities [[13], [14], [15], [16], [17]]. RES is found to be effective in diabetic nephropathy [14,18,19] and neuropathy [[20], [21], [22]] due to its antioxidant effect. Recently, RES was found to have ameliorative potential for renal carcinoma in rats in combination with SIT [23].
DPP-4 inhibitors are the most commonly prescribed drugs for the treatment of T2DM. USFDA approved DPP-4 inhibitors including alogliptin (ALO), linagliptin (LIN), saxagliptin (SAX), sitagliptin (SIT). Teneligliptin (TEN) and vildagliptin (VIL) are the DPP-4 inhibitors approved in Japan and by the European Medicines Agency (EMA) respectively. CYP2D and CYP3A are responsible for the metabolism of ALO [24,25]. LIN is 90% excreted unchanged, mainly non‐renal route of excretion [26,27]. CYP3A, is responsible for SAX metabolism [28]. CYP2C and CYP3A are responsible for the metabolism of SIT [29]. CYP3A and Flavin monooxygenases (FMOs) are responsible for metabolism of TEN [30,31]. VIL is neither a CYP 450 enzyme-substrate nor its inhibitor/inducer [32]. RES is a mechanism-based in-activator of CYP3A [33]: it inhibits CYP 3 A subfamily and 1 A subfamily in rat and human liver microsomes [34] and also moderately inhibits CYP2C and CYP2D subfamily [35]. Patients often consume herbal supplements together with prescription drugs. This is a vital concern due to the possibility of drug–herb interaction. This fact makes it imperative to investigate whether concomitant administration of RES and DPP-4 inhibitors has any effect on their plasma levels, due to possible pharmacokinetic interaction. Hence, the objective of our present study is to explore the effect of RES on the pharmacokinetics of DPP-4 inhibitors in vitro using liver microsomes (rat and human) and in vivo in Sprague Dawley rats.
Section snippets
Chemicals and reagents
Alogliptin (ALO) (>95% purity), sitagliptin (SIT) (>98% purity), saxagliptin (SAX) (>96% purity), teneligliptin (TEN) (>95% purity), vildagliptin (>95% purity), linagliptin (LIN) (>96% purity), and telmisartan (IS) (>98% purity) were procured from Cayman Chemicals (USA). Resveratrol (RES), phosphate buffer, sodium carboxymethyl cellulose and formic acid (LC-MS grade) was purchased from Sigma Aldrich (USA). Acetonitrile (LC-MS grade) was purchased from Merck (Mumbai, India). HPLC Grade water
In vitro metabolic stability study in rat and human liver microsomes
The amount of substrate at 0 min (100%) was measured and compared with the amount of substrate at different time points (0.25, 0.5, 0.75 and 1 h) based on the change in the analyte to internal standard (IS) peak-area ratio. The percentage remaining calculated from the in vitro metabolic stability for ALO, SAX, SIT and TEN and negative control (VIL, LIN) is shown in Table 1. The data (mean ± SD) of ALO, SIT, SAX and TEN alone and in combination with RES were compared by performing statistical
Discussion
There is a rising trend in the use of dietary supplements among people. Most of the dietary supplements are herbal extract and may include active phytochemicals such as RES. These phytochemicals have the potential to modulate drug-metabolizing enzymes activity, which might lead to drug-herb interactions [36]. The literature pertaining to drug-herb pharmacokinetic interactions is scarce, and very little information is available [37,38]. Cytochrome P450s is sensitive to modulation by multiple
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors would like to thank Dr. Shashi Bala Singh, Director, NIPER-Hyderabad for her motivation and support. One of the authors, Shruti Surendran, is thankful to the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, New Delhi, India, for providing a research fellowship. Authors are also thankful to the Science and Engineering Research Board (SERB), DST, New Delhi, India, for the financial support for this research work under Extra Mural Research Funding (EMR/2016/002098).
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