Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Abstract

Natural products have been used by humans since antiquity for both egregious and beneficial purposes. Regarding the latter, these products have long been valued as a rich source of phytochemicals and developed into numerous life-saving pharmaceutical agents. Today, the sales and use of natural products with purported medicinal qualities continue to increase worldwide. However, natural products are not subject to the same premarket testing requirements as pharmaceutical agents, creating critical gaps in scientific knowledge about their optimal use. In addition, due to the common misperception that "natural" means "safe," patients may supplement or replace their prescription medications with natural products, placing themselves at undue risk for subefficacious pharmacotherapy or potentially toxic exposure. Collectively, with few exceptions, researchers, health care providers, and educators lack definitive information about how to inform consumers, patients, and students in the health professions on the safe and optimal use of these products. Recognition of this deficiency by key stakeholders, including the three pillars of biomedical research-industry, academia, and government-has facilitated multiple collaborations that are actively addressing this fundamental knowledge gap. This special issue contains a collection of articles highlighting the challenges faced by researchers in the field and the use of various experimental systems and methods to improve the mechanistic understanding of the disposition and drug interaction potential of natural products. Continued refinement of existing, and development of new, approaches will progress toward the common overarching goal of improving public health. SIGNIFICANCE STATEMENT Natural products with purported medicinal value constitute an increasing share of the contemporary health care market. Natural products are not subject to the same premarket testing requirements as drug products, creating fundamental scientific knowledge gaps about the safe and effective use of these products. Collaborations among industrial, academic, and governmental researchers in multiple disciplines are anticipated to provide the definitive information needed to fill these gaps and improve public health.

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

“…As is common with botanical products, kratom products are regulated differently than FDA-approved drugs. Although not recognized as a dietary supplement according to the Dietary Supplement Health and Education Act, the regulation of kratom is not unlike that of dietary supplements ( Paine and Roe, 2018 ; Paine, 2020 ). That is, kratom products are not required to undergo extensive safety testing prior to marketing.…”

Plant‐derived virulence arresting drugs as novel antimicrobial agents: Discovery, perspective, and challenges in clinical use

“…However, evaluating the safety and efficacy of natural products is still problematic. Human clinical pharmacokinetic parameters, such as clearance and bioavailability, for the most distinct ingredients derived from natural products are unknown (Paine, 2020). Thus, these findings could not provide sufficient and accurate in vivo safety information.…”

Natural Products Inhibition of Cytochrome P450 2B6 Activity and Methadone Metabolism

“…Use of natural products such as herbals and other botanicals (Paine, 2020) is substantial and the market has grown rapidly, with sales of herbal dietary supplements in the United States exceeding $11 billion in 2020 (Smith et al, 2021). Concomitant use of prescription medicines and non-prescription herbal products is common, (Harris et al, 2022) and may result in reduced treatment effect or adverse effects (Paine et al, 2018).…”