Abstract
An aspalathin-rich green rooibos extract (Afriplex GRT™) has demonstrated anti-diabetic and hypolipidemic properties, while also moderately inhibiting CYP3A4 activity, suggesting a potential for herb–drug interaction. The present study, therefore, evaluated the effects of orally administered GRT on the pharmacokinetics of atorvastatin and metformin in Wistar rats. Wistar rats were orally treated with GRT (50 mg/kg BW), atorvastatin (40 mg/kg BW) or metformin (150 mg/kg BW) alone or 50 mg/kg BW GRT in combination with 40 mg/kg BW atorvastatin or 150 mg/kg BW metformin. Blood samples were collected at 0, 10, and 30 min and 1, 2, 4, 6, and 8 h and plasma samples obtained for Liquid chromatography-mass spectrometry (LC-MS/MS) analyses. Non-compartment and two-compartment pharmacokinetic parameters of atorvastatin and metformin in the presence or absence of GRT were determined by PKSolver version 2.0 software. Membrane transporter proteins, ATP-binding cassette sub-family C member 2 (Abcc2), solute carrier organic anion transporter family, member 1b2 (Slco1b2), ATP-binding cassette, sub-family B (MDR/TAP), member 1A (Abcb1a), and organic cation transporter 1 (Oct1) mRNA expression were determined using real-time PCR expression data normalized to β-actin and hypoxanthine-guanine phosphoribosyltransferase (HPRT), respectively. Co-administration of GRT with atorvastatin substantially increased the maximum plasma concentration (Cmax) and area of the plasma concentration–time curve (AUC0-8) of atorvastatin by 5.8-fold (p = 0.03) and 5.9-fold (p = 0.02), respectively. GRT had no effect on the plasma levels of metformin. GRT increased Abcc2 expression and metformin downregulated Abcb1a expression while the combination of GRT with atorvastatin or metformin did not significantly alter the expression of Slco1b1 or Oct1 did not significantly alter the expression of Sclo1b2 or Oct1. Co-administration of GRT with atorvastatin in rats may lead to higher plasma concentrations and, therefore, to an increase of the exposure to atorvastatin.
Highlights
Diabetes mellitus (DM), characterized by failure to maintain physiological glucose and lipid levels, is a complex metabolic disorder that affects approximately 15.5 million people in Africa (International Diabetes Federation, 2017)
Current DM treatment regimens frequently involve the use of multiple therapeutics, such as metformin combined with atorvastatin to control glycemia and dyslipidemia, thereby ensuring adequate metabolic control (Bell, 2004; Padwal et al, 2005; Matafome et al, 2011)
An aspalathin-enriched green rooibos extract (GRE) containing 18% aspalathin (Muller et al, 2012), as well as purified aspalathin has been reported to augment glucose uptake in L6 myotubes by activating 5′adenosine monophosphate-activated protein kinase (AMPK) and glucose transporter type 4 (GLUT 4) translocation to the cell membrane (Son et al, 2013; Kamakura et al, 2015)
Summary
Diabetes mellitus (DM), characterized by failure to maintain physiological glucose and lipid levels, is a complex metabolic disorder that affects approximately 15.5 million people in Africa (International Diabetes Federation, 2017). Therapeutics derived from natural products are becoming popular as alternative treatment strategies. These often include the use of extracts containing complex mixtures of bioactive phenolic compounds (Kang et al, 2012; Haddad et al, 2015; Oh, 2015; Shay et al, 2015). An aspalathin-enriched green rooibos extract (GRE) containing 18% aspalathin (Muller et al, 2012), as well as purified aspalathin has been reported to augment glucose uptake in L6 myotubes by activating 5′adenosine monophosphate-activated protein kinase (AMPK) and glucose transporter type 4 (GLUT 4) translocation to the cell membrane (Son et al, 2013; Kamakura et al, 2015). In an in vitro study, a pharmaceutical-grade green rooibos extract (Afriplex GRTTM), containing 12% aspalathin, has been shown to inhibit CYP3A4 activity (Patel et al, 2016), one of the CYPs responsible for metabolizing atorvastatin (Rowan et al, 2012)
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