SOLUBILITY AND TRANSPORTER MECHANISMS OF PHARMACOKINETIC INTESTINAL NATURAL PRODUCT-DRUG INTERACTIONS

Victoria O Oyanna

doi:10.7273/000007075

Botanical natural products have been fundamental to drug development and healthcare for centuries. They are often perceived as natural and safe alternatives or complements to pharmacotherapy. However, the simultaneous use of botanical natural products and conventional medicines can alter therapeutic efficacy or precipitate adverse effects due to changes in drug exposure. Botanicals or herbal supplements consist of multiple constituents capable of interacting with drugs through various mechanisms. Typically administered orally, both botanical and conventional medicines reach their highest concentrations in the intestinal lumen and/or enterocytes. Hence, when consumed together, there is an increased potential for direct or indirect drug interactions. Understanding the mechanistic basis of these interactions is essential for healthcare providers to offer better guidance to consumers and potentially mitigate unwanted clinical outcomes. Chapter one provides an overview of the different mechanisms underlying pharmacokinetic interactions between botanical natural products and drugs in the intestine, highlighting the influence of the physicochemical properties of the involved drug(s). It emphasizes how drug solubility, dissolution, and osmolality can potentially impact drug absorption and systemic exposure. This dissertation investigated the solubility and transporter mechanisms involved in pharmacokinetic drug interactions with popular botanical natural products, specifically green tea and goldenseal. Using a combination of in vitro and in vivo studies, we aimed to identify the mediators and mechanisms of these observed interactions. Chapter two examined the interaction between green tea and the poorly water-soluble drug raloxifene. Results demonstrated that green tea and flavan-3-gallate catechins, including (-)-epigallocatechin gallate (EGCG), significantly reduced the solubility of raloxifene in the fasted state but had no effect on the solubility of a more water-soluble drug, nadolol. This reduction in solubility corresponded to a significant decrease in the maximum plasma concentration (Cmax) of raloxifene when orally administered with green tea extract in mice, suggesting that the co-consumption of green tea can affect the pharmacokinetics of raloxifene. Th ese results warranted further assessment of another poorly water-soluble compound, amiodarone, as described in the appendix. These experiments evaluated the potential pharmacokinetic interaction between green tea and amiodarone, providing additional insight into the mechanism of reduced drug solubility by green tea. EGCG and another flavan-3-gallate catechin, (-)-epicatechin gallate (ECG), significantly decreased the solubility of amiodarone in the fasted state. In contrast, studies in mice demonstrated only modest changes in the oral pharmacokinetics of amiodarone by green tea. Chapter three examined the pharmacokinetic interaction between goldenseal and metformin, specifically how a goldenseal extract and the alkaloids berberine, (–)-β-hydrastine and hydrastinine affect the function of intestinal uptake transporters organic cation transporter 3 (OCT3), plasma monoamine transporter (PMAT), and thiamine transporter 2 (THR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters in vitro, and decreased metformin Cmax and oral bioavailability in mice. In contrast, berberine and (–)-β-hydrastine had no effect on metformin pharmacokinetics in mice, indicating other goldenseal constituents are responsible for this interaction. This research offers mechanistic information about the interactions between botanical natural products and drugs. It highlights the complexity of these interactions and emphasizes the importance of expanding the scope of natural product-drug interaction research for improved in vitro-in vivo correlations. Future studies need to carefully consider the complexity of these mechanisms and their potential clinical implications, to guide healthcare professionals in optimizing therapeutic outcomes and safeguarding patient safety.

SOLUBILITY AND TRANSPORTER MECHANISMS OF PHARMACOKINETIC INTESTINAL NATURAL PRODUCT-DRUG INTERACTIONS

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