B-CLEAR^®

The only in vitro method to predict in vivo liver disposition

B-CLEAR^®, a patented¹ sandwich-cultured hepatocyte system, is the only in vitro method to predict in vivo hepatic uptake and biliary clearance, and assess drug transporter inhibition. B-CLEAR^® surpasses other transporter assessment methods by generating data predictive of in vivo outcomes.  B-CLEAR^® is the only method to evaluate transporters as a system, permitting evaluation, function, and interplay similar to that which occurs in vivo.  For optimum in vivo predictability, B-CLEAR^® utilizes human, monkey, dog, rat and mouse hepatocytes. Qualyst counts more than half of the top-tier pharmaceutical companies and multiple innovative biotech companies as B-CLEAR^®clients.

Research using B-CLEAR^® provides valuable, actionable knowledge to:

• Differentiate compounds for candidate selections by rank ordering according to propensity for biliary excretion.
  
  
• Predict in vivo human biliary clearance potential before running clinical trials.
  
  
• Select candidates according to interspecies differences in liver uptake, hepatic accumilation, and biliary excretion.
  
  
• Identify drug-drug interactions at the level of hepatobiliary transport, and assess possible clinical implications.
  

Discover More About B-CLEAR^®

Identify and select better drug candidates with B-CLEAR^®

B-CLEAR^® identifies compounds with desirable hepatobiliary disposition properties, enabling better prediction of bioavailability, pharmacokinetics, species-specific drug dosing, and candidate selection. 

Evaluate drug transporters as a system & predict drug interactions

Identifying hepatic drug transport mechanisms is critical to understanding liver uptake, biliary excretion, drug-drug interactions, and hepatotoxicity.  Recombinant methods to study drug transporters are limited by their lack of predictability to in vivo outcomes, and their study of transporters in isolation–or at best in subsets.  B-CLEAR^® evaluates transporters as a system and predicts in vivo outcomes, identifying adverse drug-drug interaction potential and avoiding costly product development challenges. 

B-CLEAR^® mimics liver structure

B-CLEAR® maintains hepatocytes in culture between two layers of gelled collagen, which results in the formation of extensive, functional canalicular networks.  In vitro biliary clearance is calculated by differentiating between the total amount of compound taken up into hepatocytes, and the total amount of compound that is taken up and excreted into the canalicular networks.  These canalicular networks are composed of so-called “bile pockets” that are excluded from the media by tight junctions between cells (see photo).  The presence of calcium in the media is required to maintain the tight junctions sealing the bile pockets.  Incubation in media lacking calcium results in an opening of the tight junctions, and release of the contents of the bile pockets into the media, permitting quantitation of compound that has accumulated in the hepatocytes.

Carboxydichlorofluorescein is taken up by B-CLEAR^® rat hepatocytes and excreted into the canalicular networks formed between the cells.

 

 

Validated: B-CLEAR^® predicts in vivo outcomes

Qualyst has thoroughly validated the B-CLEAR^® system, including assessment of the expression of hepatic uptake and excretory transporters, localization of the transporters to the correct membrane in the hepatocyte, and the proper function of those transporters².  Control compounds are assessed in each experiment, demonstrating high reproducibility and low variability.  Most importantly, probe substrates using B-CLEAR^® have demonstrated in vitro to in vivo biliary clearance correlation for both rats and humans (see figure).

Blue: Rat in vivo biliary clearance of 11 compounds and correlation to in vitro B-CLEAR^® rat hepatocyte data (r²=0.99; Lieu et al., Drug Metab Dispos 27:637, 1999). Green: Human in vivo biliary clearance of three compounds and prediction to in vitro B-CLEAR^® human hepatocyte data (Ghibellini et al., Clin Pharmacol Ther 81:406, 2007).

Access to B-CLEAR^®

B-CLEAR^® is currently being applied by pharmaceutical and biotechnology companies in both discovery and development through several different means, including kits, services, and licensing.

B-CLEAR^® Kits

B-CLEAR^® Kits enable clients to profile compounds using B-CLEAR^® at their own facilities.  Each B-CLEAR^® Kit contains multiple plates of sandwich-cultured hepatocytes optimized for B-CLEAR^®, cell culture media, buffers and instructions for applications such as:

• Rank-ordering multiple compounds according to propensity for biliary excretion.
  
  
• Determining pharmacokinetic properties of a compound including time-dependent or concentration-dependent effects on hepatobiliary disposition.
  
  
• Identifying drug-drug interactions affecting hepatobiliary transport and reveal potential clinical implications of co-administered therapeutics.

To inquire about B-CLEAR^® Kits, please contact kits [at] qualyst [dot] com or fill out the online order form.

If you have a question about experimental design (e.g. how many kits will be required to execute your specific aims), please contact us.

B-CLEAR^® Services

Qualyst provides contract research services to profile client compounds using B-CLEAR^® at our North Carolina laboratories.  Services projects vary in size depending on scope and the client’s specific aims.  For example, they may be small, feasibility-type studies, or large, detailed projects for deep investigation of a compound’s attributes.  Qualyst then reports the results of the B-CLEAR^® analyses back to the client with collaborative interpretation of the data.  To inquire about B-CLEAR^® services at Qualyst, please contact sales [at] qualyst [dot] com or fill out the inquiry form on our contact page.

In addition, Qualyst has partnered with Covance Laboratories, Inc., one of the world's largest and most comprehensive drug development services companies, to offer B-CLEAR^® as part of Covance’s broad array of pharmacokinetic service offerings.  To inquire about B-CLEAR^® services offered and performed by Covance, please send an email to info [at] Covance [dot] com or call +1-888-COVANCE.

B-CLEAR^® Licensing

Clients desiring high volume B-CLEAR^® profiling may license the system for technology transfer and non-exclusive rights to perform B-CLEAR^® at designated sites.  A license provides access to the B-CLEAR^® intellectual property¹, the training of user scientists, and transfer to and installation of B-CLEAR^® at designated client sites.  Special pricing for B-CLEAR^® Kits is offered to B-CLEAR^® licensees.  To inquire about obtaining a license to B-CLEAR^® for internal research and development, please contact sales [at] qualyst [dot] com or fill out the inquiry form on our contact page.

References

Please click here to download a list of references relevant to B-CLEAR^®

Technical Application Bulletins

B-CLEAR^®: Modifications for Protein in Dose Solution: Describes the use of protein in B-CLEAR^® uptake/efflux experiments.

B-CLEAR^®: Cholestatic Hepatotoxicity: Describes the use of B-CLEAR^® uptake/efflux experiments to evaluate a compound’s potential to cause cholestatic hepatotoxicity.