Bile acids in drug induced liver injury: Key players and surrogate markers

Schadt, Heiko S.; Wolf, Armin; Philippe, François; Chibout, Salah-Dine; Merz, Michael; Kullak‐Ublick, Gerd A.

doi:10.1016/j.clinre.2015.12.017

Cited by 66 publications

(50 citation statements)

References 100 publications

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“…This incident prompted the addition of standardized language in early clinical protocols to collect, retain and examine serum samples, leftover from the conduct of safety labs, for exploratory safety biomarker work in with subject consent in advance of the clinical trial start. Only in this way can we truly establish whether drug‐induced liver injury is causally or only associated with alterations in bile acid homeostasis and the potential use of bile acids as surrogate markers …”

Section: Discussionmentioning

confidence: 99%

“…Only in this way can we truly establish whether drug-induced liver injury is causally or only associated with alterations in bile acid homeostasis and the potential use of bile acids as surrogate markers. 51 In summary, the incidence of transaminase elevations in human healthy subjects treated with PF-04895162 led to its termination from clinical development before its therapeutic potential could be fully examined. Although preclinical safety assessment studies did not highlight the liver as a target organ, retrospective investigation using in vitro assays designed to detect potential mechanisms of liver injury demonstrated combined BSEP and mitochondrial inhibition as potential mechanisms that are recognized as dual risk factors for human DILI.…”

Section: Examination Of Residual Plasma Pharmacokinetic Samples Formentioning

confidence: 99%

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Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Aleo

Aubrecht

Bonin

et al. 2019

Pharmacology Res & Perspec

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During a randomized Phase 1 clinical trial the drug candidate, PF‐04895162 (ICA‐105665), caused transaminase elevations (≥grade 1) in six of eight healthy subjects treated at 300 mg twice daily for 2‐weeks (NCT01691274). This was unexpected since studies in rats (<6 months) and cynomolgus monkeys (<9 months) treated up to 100 mg/kg/day did not identify the liver as a target organ. Mechanistic studies showed PF‐04895162 had low cytotoxic potential in human hepatocytes, but inhibited liver mitochondrial function and bile salt export protein (BSEP) transport. Clinical relevance of these postulated mechanisms of liver injury was explored in three treated subjects that consented to analysis of residual pharmacokinetic plasma samples. Compared to a nonresponder, two subjects with transaminase elevations displayed higher levels of miRNA122 and total/conjugated bile acid species, whereas one demonstrated impaired postprandial clearance of systemic bile acids. Elevated taurine and glycine conjugated to unconjugated bile acid ratios were observed in two subjects, one before the onset of elevated transaminases. Based on the affinity of conjugated bile acid species for transport by BSEP, the profile of plasma conjugated/unconjugated bile acid species was consistent with inhibition of BSEP. These data collectively suggest that the human liver injury by PF‐04895162 was due to alterations in bile acid handling driven by dual BSEP/mitochondrial inhibition, two important risk factors associated with drug‐induced liver injury in humans. Alterations in systemic bile acid composition were more important than total bile acids in the manifestation of clinical liver injury and may be a very early biomarker of BSEP inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Examination Of Residual Plasma Pharmacokinetic Samples Formentioning

confidence: 99%

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Aleo

Aubrecht

Bonin

et al. 2019

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…BAs are synthesized in the liver from cholesterol and are secreted into the bile canaliculi through the canalicular membrane, a process driven by the bile salt export pump (BSEP) (Schadt et al, 2016). BAs are biomarkers of DILI due to their amphiphilic and strong emulsifying detergent properties, which may damage the integrity of cell membrane and result in cytotoxic effects.…”

Section: Bile Acids (Bas)mentioning

confidence: 99%

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Jiang

et al. 2020

Front. Pharmacol.

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Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.

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“…Drug-induced liver injury is the most frequent key cause for termination of drug development during or after preclinical studies and for drug withdrawal from the market (Schadt et al, 2016). Despite exhibiting excellent immunosuppressive and anti-tumor activities, TP has been greatly restricted in clinical application on the basis of a severe and cumulative hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Activation of Sirt1/FXR Signaling Pathway Attenuates Triptolide-Induced Hepatotoxicity in Rats

et al. 2017

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Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis. The aims of this study were to determine whether Sirt1/FXR signaling pathway plays a critical role in TP-induced hepatotoxicity. Our study revealed that the intragastric administration of TP (400 μg/kg body weight) for 28 consecutive days increased bile acid accumulation, suppressed hepatic gluconeogenesis in rats. The expression of bile acid transporter BSEP was significantly reduced and cholesterol 7α-hydroxylase (CYP7A1) was markedly increased in the TP-treated group, whereas the genes responsible for hepatic gluconeogenesis were suppressed in the TP-treated group. TP also modulated the FXR and Sirt1 by decreasing its expression both in vitro and in vivo. The Sirt1 agonist SRT1720 and the FXR agonist obeticholic acid (OCA) were used both in vivo and in vitro. The remarkable liver damage induced by TP was attenuated by treatment with either SRT1720 or OCA, as reflected by decreased levels of serum total bile acids and alkaline phosphatase and increased glucose levels. Meanwhile, SRT1720 significantly alleviated TP-induced FXR suppression and FXR-targets involved in hepatic lipid and glucose metabolism. Based on these results, we conclude that Sirt1/FXR inactivation plays a critical role in TP-induced hepatotoxicity. Moreover, Sirt1/FXR axis represents a novel therapeutic target that could potentially ameliorate TP-induced hepatotoxicity.

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Bile acids in drug induced liver injury: Key players and surrogate markers

Cited by 66 publications

References 100 publications

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Activation of Sirt1/FXR Signaling Pathway Attenuates Triptolide-Induced Hepatotoxicity in Rats

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