While in 1991 the major cause of attrition in drug discovery was pharmacokinetics, however by 2000 increased knowledge of the factors influencing the ADME properties plus increasingly sophisticated in vitro and in vivo assays had dramatically reduced this as the cause for attrition. In contrast the rate of attrition due to toxicity increased over the same time period (Nature Reviews Drug Discovery 3, 711-716 (August 2004)).
HERG activity inhibition of the HERG channel is linked to QT prolongation in vivo and subsequent sudden cardiac death.
Mutagenicity (In progress)
Drug-Drug Interactions (DDI)
Many drug interactions are due to the impact one drug can have on the metabolism of a second drug’s metabolism. One major system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases. This system may be affected by either enzyme induction or enzyme inhibition or in some cases both.
- Enzyme induction - Drug A induces the body to produce more of an enzyme which metabolises drug B. This reduces the effective concentration of drug B, which may lead to loss of effectiveness of drug B. Drug A effectiveness may or may not altered.
- Enzyme inhibition - Drug A inhibits the enzyme metabolising drug B, thus an elevation of drug B occurs possibly leading to an overdose.
- Bioavailability - Drug A influences the absorption of drug B perhaps by blocking active uptake mechanism or inhibiting active transport mediated excretion in the gut.
Hepatotoxicity
Drug-induced liver injury is a major health problem that impacts the pharmaceutical industry, drug regulatory agencies and doctors. Drug induced hepatotoxicity accounts for more than 50% of acute liver failure, and is the major cause of drug withdrawals. Because of the significant patient morbidity and mortality, many drugs have been withdrawn from the market, including bromfenac, ebrotidine, and troglitazone. Other hepatotoxic drugs, such as risperidone, trovafloxacin, and nefazodone,have been assigned “black box” warnings.
Idiosyncratic toxicity Adverse drug reactions, mechanisms and strategies to avoid them.
Worth reading The Identification of Toxicophores for the Prediction of Mutagenicity, Hepatotoxicity and Cardiotoxicity
Last Update 11 Sept 2009
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