Study uses fresh method to evaluate botanical-drug interactions

A whole cell model using Transporter-certified hepatocytes in sandwich culture has demonstrated that false positives might be a risk with the traditional method of analysis

BioIVT’s 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).

The paper describes a research collaboration by BioIVT and P&G based on studies conducted in BioIVT’s laboratory in Durham, NC with Boswellia serrata.

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, with US retail sales reaching US$14.6 million in 2017 and currently ranked at 19th of the top 40 list of best-selling herbal supplements.

“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,” 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.”

Method accuracy

BioIVT and P&G’s study compared two in vitro methods to evaluate the inhibitory effects of B.serrata on CYP enzymatic activity. First was the conventional pooled human liver microsomes and next was a whole cell model using Transporter-certified hepatocytes in sandwich culture.

The study 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.

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 of 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.”

This led Brouwer to 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. Meaning it can 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.

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