Study compares two in vitro liver methods to determine which one best predicts BDIs
Westbury, NY – May 2, 2019 – BioIVT, a leading provider of research models and services for drug and diagnostic development, today announced that its ADME-Tox team has co-authored a second peer-reviewed paper investigating the potential for clinically-relevant botanical-drug interactions (BDIs) with toxicology colleagues at The Procter & Gamble Company (P&G).1 The paper describes a research collaboration by BioIVT and P&G based on studies conducted in BioIVT’s laboratory in Durham, NC.
This new study investigates potential BDIs with Boswellia serrata (Indian Frankincense), a botanical that is used as an anti-inflammatory supplement. The popularity of products containing B. serrata extract is growing. US retail sales of B. serrata reached $14.6 million in 20172 and it continues to move up the top 40 list of best-selling herbal supplements; it is currently ranked number 19.2
“As the use of botanicals, such as B. serrata, increases so does the need to investigate the potential for BDIs. This is especially true because the use of botanical supplements is highest amongst the elderly (those aged 65 years and older), who are more likely to have comorbidities and take multiple medications,”3-5 said Amy Roe, PhD, DABT, lead author and principal toxicologist at P&G. “Our primary goal with this study was to help determine the most reliable in vitro method for predicting BDIs.”
BioIVT and P&G’s study compared two in vitro methods – conventional pooled human liver microsomes and a whole cell model using TRANSPORTER CERTIFIED™ hepatocytes in sandwich culture – to evaluate the inhibitory effects of B. serrata on CYP enzymatic activity. It focused specifically on CYP2C9 and CYP3A4/5 as those enzymes had been shown in in vitro studies to be the most potently inhibited by B. serrata. CYP enzymes play an important role in drug metabolism, so inhibiting them can change the effectiveness and safety of some drugs. For example, CYP2C9 is the primary CYP isoform involved in the clearance of the nonsteroidal anti-inflammatory drug (NSAID), ibuprofen.6
While the microsomal liver method predicted potent CYP inhibition by B. serrata, the sandwich-cultured whole cell model predicted much less inhibition potential.
“Although we are not aware of any clinical studies investigating potential BDIs with B. serrata, the large volume of sales of this botanical, seemingly without adverse events, tends to suggest that the microsomal model may be overly conservative, potentially leading to false positives,” said Kenneth Brouwer, VP, ADME-Tox at BioIVT and a study co-author. “The microsomal studies may overestimate the interaction potential because they lack the full complement of metabolic enzyme and transporter functions. Therefore, we believe that the sandwich-cultured human hepatocytes model, which incorporates cellular uptake, efflux, metabolism, and regulatory function, serves as a more accurate predictor of in vivo effects. It can also be employed to investigate both potential drug-drug interactions and BDIs.”
Although the sandwich-cultured human hepatocyte data suggested that the risk of BDIs with B. serrata was generally low, the authors urged caution when combining it with drugs that have a narrow therapeutic window, such as warfarin, or drugs that are sensitive substrates for CYP2C9, such as the NSAID diclofenac.
Regulatory Oversight
The US Food and Drug Administration (FDA) is also focusing on botanicals and the potential risk for BDIs. In February 2019, FDA announced increased efforts to strengthen regulatory oversight of dietary supplements. Included in this initiative was the formation of the Botanical Safety Consortium, a public-private partnership that will investigate “novel ways to use cutting-edge toxicology tools, including alternatives to animal testing, to promote the goals of safety and effectiveness we share with consumers and other stakeholders.7”
BioIVT supports this initiative and is committed to developing products and methods that will help researchers predict potential risks and benefits of dietary supplements and enable consumers to make informed decisions about these products.