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BioAssay: AID 678721

Metabolic stability in human liver microsomes assessed as GSH adduct formation at 100 uM after 90 mins by HPLC-MS analysis

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and more ..
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 Tested Compounds
 Tested Compounds
All(107)
 
 
Active(105)
 
 
Unspecified(2)
 
 
 Tested Substances
 Tested Substances
All(107)
 
 
Active(105)
 
 
Unspecified(2)
 
 
 Related BioAssays
 Related BioAssays
AID: 678721
Data Source: ChEMBL (835860)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2013-05-16
Modify Date: 2013-07-08

Data Table ( Complete ):           Active    All
BioActive Compounds: 105
Description:
Title: Preclinical strategy to reduce clinical hepatotoxicity using in vitro bioactivation data for >200 compounds.

Abstract: Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of #100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding #200 pmol eq/mg protein tended to be hepatotoxic (# 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.
(PMID: 22931300)
Comment
Putative Target:

ChEMBL Target ID: 22226
Target Type: UNCHECKED
Pref Name: Unchecked
Confidence: Default value - Target unknown or has yet to be assigned
Relationship Type: Default value - Target has yet to be curated
Categorized Comment
ChEMBL Assay Type: ADMET

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Assay Tissue: Liver

ChEMBL Assay Subcellular Fraction: Microsomes

Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Stabilty activity commentStabilty activity commentString
2Stabilty standard flagStabilty standard flagInteger
3Stabilty qualifierStabilty qualifierString
4Stabilty published valueStabilty published valueFloat
5Stabilty standard valueStabilty standard valueFloat

Data Table (Concise)
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