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THE PHARMA REVIEW (JANUARY - FEBRUARY 2012)

Xenobiotic Acyl CoA Thioester Formation-A Translational Factor Influencing Susceptibility to Adverse Drug Reactions in Man: A Review

Himansha Singh

Abstract: From the time unknown, invention and innovation have been vital for human development. In healthcare sector, pharmaceutical companies have worked extensively on developing new entities that have become therapies for diseases. However, they face problem in the poor revenue generation in developing a new drug, mostly due to delay in FDA approval, withdrawal of drugs or its rejection in post- marketing surveillance. Several drugs, mostly acidic, are discontinued from the market due to occurrence of idiosyncratic drug reactions (IDRs) in past decades. IDRs are troublesome as they are mainly seen after the drug is launched in the market. It is very difficult to predict their occurrence pre-clinically. However, metabolism of carboxylic acid is envisaged as its potential contributor. Two pathways, involved in carboxylic acid metabolism, may lead to chemically reactive metabolites: I) Acyl glucuronide formation and II) Acyl-CoA thioester formation. Several studies have evidenced toxicity due to glucuronides in most of the drugs, whereas, little information is documented about thioesters. Point of interest is that high reactivity and involvement of xenobiotic thioesters in crucial biological pathways such as β-oxidation, etc., makes it interesting to investigate their disposition. Evidently, their involvement in toxicity is significant and requires exploration and xenobiotic thioesters should be handled as ‘structural alerts’ in causing adverse drug reactions (ADRs).

 
Drug failure and economical consequences: In healthcare sector, pharmaceutical companies have worked extensively on developing new entities that have become therapies for diseases. However, poor revenue is still a problem, mostly due to withdrawal of drugs or its rejection in post- marketing surveillance1. Different surveys estimated the approximate cost for launching a drug in market to be US$ 114 million between 1970 and 19822, 802 US$ million in 20033 and US$ 1 billion in 20104
In 2000, 30% drugs were withdrawn due to poor drug safety6. Even in 2010, the total estimated revenue loss to the companies due to discontinuation of the drug was approximately 74 US$ billion7. The root cause of attrition is lack of efficacy, toxicology and clinical safety. Suitable measures are required to eliminate the percentage of drug failure. For instance, providing strong evidences to show proof of mechanism and proof of concept, identification of toxic metabolites, and use of appropriate animal models, which can mimic the effect of drug in humans effectively,.

 

 

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