Pharmacokinetics
A
B
Figure 1: Inhibition of CYP3A4/5 by SSE (A) or SCE (B), without preincubation (l
professionals about dietary supplement use, despite media attention warning about potential BDIs. We believe that providing information on potential BDIs can facilitate informed decision- making by consumers and healthcare providers.
Conventional methods to investigate BDIs are inadequate The scientific literature includes numerous reports of the potential of botanical extracts and/or specif- ic phytochemical constituents to inhibit cyto- chromes P450 enzymes (CYP450). These studies are typically done with isolated in vitro systems such as liver microsomes; thus, CYP450 inhibition is the only interaction mechanism studied. There are also reports of quite potent inhibition of CYP450s, particularly when individual phyto- chemical constituents are used in these assays. The interaction of botanical extracts with transporter proteins is also studied using in vitro systems such as Caco-2 cells. Unfortunately, follow-on studies using more physiologically-relevant in vitromodels and/or human clinical studies are rarely conducted. There is also a paucity of data on the ability of botanical extracts or phytochemical constituents to induce CYP450 enzymes. For the few botanical extracts where interaction
potential has been studied in both in vitro and clin- ical studies, the correlation has been poor3. In a recent review, Sprouse and van Breemen compared results from available preclinical data (largely in vitro) with clinical results across a number of botanicals or phytochemical complexes3. Only in a few examples, such as echinacea, garlic, goldenseal and St John’s wort, do in vitro studies predict sim-
Drug Discovery World Fall 2018
) and with preincubation (n
)
ilar findings on CYP450s to clinical studies. The in vitro systems used in these studies are even less likely to predict clinically-meaningful changes. The aforementioned review acknowledges that
there are a number of explanations for the poor correlation of in vitro data to clinical findings. It is difficult to compare botanical materials across studies to ensure similarity of test article, and the solubility of the complex mixtures represented by botanical extracts can be challenging to study in certain in vitro systems. The authors also mention that the in vitro model(s) used, and the lack of including CYP450 induction in addition to inhibi- tion assessments, can impact the ability to predict clinical relevance. An additional complication with BDI predic-
tions based on these simplistic screening-level in vitro studies is that the data are incorporated into safety-related databases and publicly-available websites without critical review. This may cause undue concern for consumers and healthcare pro- fessionals regarding the concomitant use of certain dietary supplements with prescription medicines. Likewise, even scientific reports, such as the review by Sprouse and van Breemen, can inappropriately impugn the utility of in vitro metabolic and trans- porter systems to predict if and when clinical fol- low-up studies are warranted.
Our strategy: investigate a known BDI by treating a botanical mixture as a single entity Due to the above-mentioned challenges, we want- ed to develop an alternative approach for studying BDIs that would improve the ability of in vitro models to predict clinically-meaningful changes in
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