Researchers develop tool to predict drug-induced cholestasis
Effort involved separating medicines based on effects on bile acid clearance
Researchers have developed a tool that can distinguish medications that result in cholestasis from those that don’t, based on their effects on key bile acid clearance processes.
Cholestasis occurs when the flow of the digestive fluid bile from the liver to the intestines slows or stops. Bile acids are the main components of bile.
Because the compounds flagged by the study will likely carry a risk of drug-induced cholestasis, “their identification at an early preclinical stage could prevent not only the development of adverse drug reactions in the clinics, but also major investments in clinical studies by pharmaceutical companies,” the researchers wrote.
The study, “Drug-induced cholestasis (DIC) predictions based on in vitro inhibition of major bile acid clearance mechanisms,” was published in the Archives of Toxicology.
Impaired bile flow in cholestasis causes bile to accumulate to toxic levels in the liver, where it’s produced, and leak into the bloodstream, triggering symptoms such as pruritus, or itching. Over time, its buildup can result in liver scarring and liver failure.
Medications that cause drug-induced cholestasis (DIC) include certain antibiotics such as penicillin, birth control pills, hormone-containing medications, and some antipsychotics. Some of the medications may interfere with mechanisms that clear bile from the liver, leading to cholestasis.
Suppressing BSEP, the main transporter of bile components out of liver cells, “has often been implicated as the driver risk factor of DILI [drug-induced liver injury],” but “not all [cholestasis-inducing] drugs are BSEP inhibitors [suppressors], and BSEP inhibition is not always predictive of DILI potential,” the researchers wrote. “Considering the complexity of bile acid regulation that involves over a dozen processes,” it’s possible that “the causes of DIC are multifactorial, and single process inhibition is a less adequate predictor of DIC.”
What medications result in drug-induced cholestasis?
A research team in Switzerland sought to develop a modified version of a previous DIC predictive model, called the 1/R value approach, that incorporated in vitro inhibition data and human drug exposure data from the literature. In vitro studies are those conducted in laboratory conditions outside of living organisms.
The tool was designed to predict which medications may lead to DIC based on “the overall inhibition potential of a drug towards all processes that drive … bile acid disposition,” wrote the researchers, who analyzed available data on the effects of 47 marketed drugs on the function of 14 proteins known to regulate bile acid balance, five involved in bile metabolism and nine bile transporters. The selected drugs had various modes of action and different degrees of DIC observed in the clinic.
A 1/R score of 1 meant the tested drug didn’t interfere with any bile clearance processes and therefore had no DIC risk, while scores greater than 1 indicated bile acid accumulation inside liver cells due to potent blockage of bile clearance mechanisms by the drug and a risk of DIC.
Based on the model, 37 had DIC risk and 10 had no concern. The drugs with the highest scores were the anti-HIV medication ritonavir (1/R score, 1.121), and benzbromarone (1/R score, 1.094), a treatment for gout, a disease marked by joint swelling and pain.
The tool could distinguish between medications that had the potential to cause DIC and those without DIC risk with an accuracy of 91%, indicating the “1/R model was able to precisely detect a large fraction of compounds with associated [DIC] concern,” wrote the researchers, who then sought to determine the best combination of minimum bile clearance processes, while maintaining the model’s predictive performance.
Isolating the risk of DIC
Combining the suppression of OATP1B1, a transporter protein that can remove excess bile acids from liver cells, and the time-dependent blockage of CYP3A4, a protein involved in detoxifying bile acids, resulted in the highest predictive ability, at 95%.
High prediction values were also obtained when OATP1B1 and CYP3A4 inhibition data were combined with those from BSEP, MDR3, or MRP2, three proteins that shuttle bile out of liver cells into the tubes called bile ducts that carry bile to the intestines.
Lastly, researchers calculated prediction values of 1/R models based on individual bile clearance processes, including bile uptake into liver cells, metabolism, or secretion from liver cells.
All the models showed “equivalent results to the revised 1/R,” except for the model based only on NTCP, a protein involved in the reuptake of bile acids from the blood, which showed significantly lower predictive ability.
“Our results support literature findings showing that BSEP inhibition alone is not a sufficient predictor to identify [DIC] risk pre-clinically,” the researchers wrote, adding the findings “point toward a rather [combinatory] effect of the key [bile] clearance processes” in developing cholestasis.
“We developed an integral and quantitative model for DIC prediction which is first of its kind regarding incorporating all aspects of intrinsic clearance of bile acids to predict DIC,” the researchers wrote. “The performance of the resulting model was very satisfactory, even after its simplification.”
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