Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development

Thompson, Richard A.; Isin, Emre M.; Li, Yan; Weaver, Richard J.; Weidolf, Lars; Wilson, Ian D.; Claesson, Alf; Page, Ken; Dolgos, Hugues; Kenna, J. Gerry

doi:10.1016/j.cbi.2010.11.002

Cited by 93 publications

(100 citation statements)

References 42 publications

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“…This observation is perhaps not surprising, because in vitro potency data take no account of differences in C max, u (which varied markedly among the tested drugs) or drug kinetics (which were not considered in the analysis). Furthermore, because hBSEP inhibition is one of numerous potential DILI mechanisms, evaluation of this liability in isolation should not be expected to provide a reliable overall assessment of the DILI liability of any individual molecule (Thompson et al, 2011). It may also be significant that the DILI severity categories used in our analysis primarily reflect regulatory outcome and not the relative DILI severities caused by the individual drugs or their incidence.…”

Section: Discussionmentioning

confidence: 96%

“…hBSEP inhibition needs to be considered as one of numerous potential mechanisms that have been implicated in DILI, and liver injury caused by individual drugs in humans may involve multiple mechanisms acting synergistically in susceptible patients. Other contributory mechanisms include reactive metabolite formation, mitochondrial injury, and immune activation (Abboud and Kaplowitz, 2007;Greer et al, 2010;Thompson et al, 2011). Published data have implicated some or all of these mechanisms in DILI caused by a number of the tested drugs, some of which were found to inhibit hBSEP [e.g., flutamide (Fau et al, 1994) and troglitazone ] and some that were not [e.g., nitrofurantoin (Czaja, 2011) and valproate (Björnsson, 2008)].…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Inhibition of the Bile Salt Export Pump Correlates with Risk of Cholestatic Drug-Induced Liver Injury in Humans

Dawson¹,

Stahl²,

Paul³

et al. 2011

Drug Metab Dispos

294

339

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ABSTRACT:Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

In Vitro Inhibition of the Bile Salt Export Pump Correlates with Risk of Cholestatic Drug-Induced Liver Injury in Humans

Dawson¹,

Stahl²,

Paul³

et al. 2011

Drug Metab Dispos

294

339

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“…In many cases, reactive metabolites are also associated with idiosyncratic liver injury. 18,28,46,47 However, on the basis of the possible correlation between reactive metabolites and idiosyncratic drug reactions, formation of a large amount of reactive metabolites is regarded as a significant liability for a drug candidate in the preclinical stages. Increased attention is needed to improve our ability to predict whether metabolites remain inside the hepatocyte during the initial drug screening process, which provides valuable information for the clinical trials of drug candidates.…”

Section: Discussionmentioning

confidence: 99%

Detection of nanolevel drug metabolites in an organotypic culture of primary human hepatocytes and porcine hepatocytes with special reference to a two-compartment model

Açıkgöz¹,

Giri²,

Bader³

2012

IJN

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Abstract:The quantification of drug metabolites produced during drug metabolism is a growing concern for the pharmaceutical industry, regulatory agencies such as the US Food and Drug Administration, the European Medicines Agency, and others. As 70% of drugs are known reactive metabolites and have black box warnings, they are a major cause of drug-induced injury and lead to drug attrition in early or late clinical stages. According to a 2006 survey report of pharmaceutical companies, drug-induced liver injury was ranked first in terms of adverse events, and it remains the most common reason for restriction or withdrawal of a drug from the market by the Food and Drug Administration. Although there are many reasons underlying drug-induced liver injury, one of the most important is liver failure induced by drug metabolites. Generally, a drug produces metabolites that may bind to cellular molecules and trigger a toxicological effect, cause serious adverse drug reactions, or alter cellular functions. Experimental cellular models that attempt to qualify drug metabolites from cell cultures rely on human plasma and urine obtained from clinical trials and supernatant during early in vitro experiments. However, there is a lack of information about the quantification of drug metabolites inside human hepatocytes, where the drug is extensively metabolized. To overcome this limitation, we used the highly accepted, gold standard organotypic cellular model of primary human hepatocytes to investigate and quantify the parent drug, as well as drug metabolites inside human hepatocytes and outside human hepatocytes to evaluate the quantity of drug metabolites, which are assumed to have remained inside the primary human hepatocytes. We refer to this as a two-compartment model, where one compartment is supernatant compared with in vivo hepatic blood circulation, and the other is inside the hepatocyte cell compared with the inside of in vivo human liver. We detected the nanoconcentrations of all major metabolites (desmethyldiazepam, temazepam, and oxazepam) of the diazepam drug, both inside the cells (matrix) and outside the hepatocyte cells (supernatant) at different time points (primary human hepatocytes: 0, 1, 2, 4, 8, and 24 hours; primary porcine hepatocytes: 0, 1, 2, 5, and 24 hours) during biotransformation in an organotypic sandwich cellular model. Although it is difficult to detect tissue distribution of metabolites in humans, we strongly recommend testing in a two-compartment model of primary human hepatocytes, as nonhuman models may not reflect human metabolism. Preclinical drug screening assessment tests that use this two-compartment strategy may facilitate safer registration of new drug candidates.

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“…Important drug-related adverse processes which can initiate idiosyncratic DILI include formation of chemically reactive metabolites, injury to mitochondria, and inhibition of the activity of the bile salt export pump (BSEP), which mediates efflux of toxic bile salts from hepatocytes into bile [6][7][8]. The susceptibility factors that explain why only some patients develop DILI are less well defined, although it is clear that these can include activation of both innate and adaptive immune responses [9].…”

Section: Introductionmentioning

confidence: 99%

“…These assays can be used during drug discovery, to enable early identification and deselection of compounds with high propensity to cause DILI and other serious adverse reactions [6][7][8]. Many different methodologies have been described, and are used routinely in pharmaceutical companies.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

Kenna

Waterton

Baudy

et al. 2018

Methods in Pharmacology and Toxicology

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Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and druginduced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug-drug interactions mediated via hepatobiliary transporter perturbation.

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Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development

Cited by 93 publications

References 42 publications

In Vitro Inhibition of the Bile Salt Export Pump Correlates with Risk of Cholestatic Drug-Induced Liver Injury in Humans

In Vitro Inhibition of the Bile Salt Export Pump Correlates with Risk of Cholestatic Drug-Induced Liver Injury in Humans

Detection of nanolevel drug metabolites in an organotypic culture of primary human hepatocytes and porcine hepatocytes with special reference to a two-compartment model

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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