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BioAssay: AID 678712

Inhibition of human CYP1A2 assessed as ratio of IC50 in absence of NADPH to IC50 for presence of NADPH using ethoxyresorufin as substrate after 30 mins

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(220)
 
 
Active(161)
 
 
Inconclusive(44)
 
 
Unspecified(15)
 
 
 Tested Substances
 Tested Substances
All(223)
 
 
Active(164)
 
 
Inconclusive(44)
 
 
Unspecified(15)
 
 
AID: 678712
Data Source: ChEMBL (835851)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2013-05-16
Modify Date: 2014-05-27

Data Table ( Complete ):           Active    All
Target
Sequence: RecName: Full=Cytochrome P450 1A2; AltName: Full=CYPIA2; AltName: Full=Cytochrome P(3)450; AltName: Full=Cytochrome P450 4; AltName: Full=Cytochrome P450-P3
Description ..   
Protein Family: Cytochrome P450
Comment ..   

Gene:CYP1A2     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 161
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)
Categorized Comment
Assay Type: ADME

Assay Data Source: Scientific Literature

BAO: Assay Format: biochemical format

Target Type: Target is a single protein chain

Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Inhibition activity commentInhibition activity commentString
2Inhibition standard flagInhibition standard flagInteger
3Inhibition qualifierInhibition qualifierString
4Inhibition published valueInhibition published valueFloat
5Inhibition standard valueInhibition standard valueFloat
6Ratio IC50 activity commentRatio IC50 activity commentString
7Ratio IC50 standard flagRatio IC50 standard flagInteger
8Ratio IC50 qualifierRatio IC50 qualifierString
9Ratio IC50 published valueRatio IC50 published valueFloat
10Ratio IC50 standard valueRatio IC50 standard valueFloat

Data Table (Concise)
Classification
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