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WCP2014 13-18 July 2014

The section contributed to several symposia in the IUPHAR2014 programme and also held a business meeting during the meeting to elect some new officers and members of the executive board. An important feature of our participation in this meeting involved four symposia which we proposed jointly with the Pharmacogenetics Section. We are grateful to the conference organisers for accepting all four symposia which were each well attended with some interesting discussion between the speakers and the audience.

Details of the symposia were as follows:

(i) Epigenetic regulation of drug metabolizing enzymes and transporters chaired by Ingolf Cascorbi with Magnus Ingelman-Sundberg, Ingolf Cascorbi and Matthias Schwab as speakers.
(ii) Pharmacogenetics in infectious disease chaired by Ann Daly with Pedro Gil, Adalberto Santos and Eleni Aklillu as speakers.
(iii) Role of drug transporters in interindividual variations in drug response chaired by Matthias Schwab with Matthias Schwab, Frans Russel and Christoph Funk as speakers.
(iv) Understanding drug-induced liver injury: CYP450 and the immune system chaired by Allan Rettie with James Lewis, Jack Uetrecht and Ann Daly as speaker

ICT Congress, Seoul, Korea

Thurs 4th July 2013

 Joint symposium sponsored by IUTOX and IUPHAR

Active Metabolites: Potential Target for New Drug Discovery and Toxicity

Chairs: Allan E Rettie (University of Washington, USA) & Dafang Zhong (Chinese Academy of Sciences, China)

The role of reactive metabolite formation in adverse drug reactions: Dominic Williams (University of Liverpool, UK)
Mechanisms of drug-drug interactions involving amiodarone metabolites: roles of irreversible and time-dependent inhibition: Allan E Rettie (University of Washington, USA)
Metabolic bioactivation potentially related to toxicities of some herbal drug components: Dafang Zhong (Chinese Academy of Sciences, China)
Genetic factors affecting metabolism to reactive intermediates in idiosyncratic hepatotoxicity: Ann K Daly (Newcastle University, UK)

Symposium summary

Metabolites of drugs and other xenobiotics are intrinsically linked with therapeutic response and toxicity. A mechanistic understanding of active and reactive metabolite formation can aid efforts to optimise drug therapy.  Additionally, evaluation of metabolite exposure during drug development by the pharmaceutical industry is an increasing component of licensing regulations.  This IUPHAR-sponsored symposium addressed all the foregoing considerations with lectures from four internationally recognized scientists from the UK, USA and China.  Symposium speakers discussed advances in our understanding of the diversity of drug bioactivation processes for both marketed drugs and herbal products as well as the identification of genetic factors that influence drug-induced liver injury.

The symposium (Active Metabolites: Potential Target for New Drug Discovery and Toxicity) was chaired by Drs. Allan Rettie (University of Washington, Seattle) and Dafang Zhong (Chinese Academy of Sciences, Shanghai) and designed to be of interest to a broad array of conference attendees. The session was opened by a comprehensive presentation from Dr. Dominic Williams (University of Liverpool) who discussed the role of reactive metabolites in adverse drug reactions (ADRs).  Dr. Williams began by emphasising the UK burden of ADRs, with 7% of patients admitted to hospital due to and ADR and 20% of in-patients have their hospital stay lengthened due to an ADR. Dr Williams then discussed mechanisms by which hepatic ADRs can arise and focused upon the example of nefazodone, an antidepressant that was withdrawn after 55 cases of liver failure. Dr Williams presented data showing that nefazodone can be bioactivated by cytochrome P450, through covalent binding and nucleophilic trapping of reactive metabolites in the form of mono- and di-hydroxy glutathione adducts. However, inhibition of 450, in fact, enhanced cytotoxicity towards rat hepatocytes, whilst inhibiting metabolism and covalent binding. These data indicate that although nefazodone can form reactive metabolites which irreversibly bind to protein, it is the parent compound which causes the toxicity.

Dr. Rettie then spoke to the formation of inhibitory metabolites of the cardiac drug, amiodarone, which is well recognised to cause drug interactions with numerous co-administered drugs that result in potentiation of the ‘victim’ drug’s pharmacology. He described his group’s research on the inhibitory potential of several N-dealkylated metabolites and concluded from in vitro data that much of the inhibition seen in vivo was likely a consequence of formation of an inhibitory di-desalkyl metabolite, which despite being a minor quantitative product, is a potent Type II inhibitor of several P450 enzymes.  Minimising the N-dealkylation pathway could be a strategy for improving the drug interaction profile of amiodarone analogues.

Dr. Zhong highlighted the potential for metabolic bioactivation of some natural products.  Herbal remedies are often a starting point for drug development but their natural origin does not preclude metabolism-related toxicities.  5-O-Caffeoylquinic acid (5-CQA) is one of the major bioactive ingredients in some Chinese herbal injections. Occasional anaphylaxis has been reported for these injections during their clinical use, possibly caused by reactive metabolites of 5-CQA. Dr. Dafong’s study aimed at characterising the bioactivation pathways of 5-CQA and the enzymes involved. The high reactivities of the ortho-benzoquinone metabolite and α,β-unsaturated carbonyl group of 5-CQA to nucleophiles were demonstrated. Different pathological situations and COMT activities in patients may alter the bioactivation extent of 5-CQA.

Finally, Dr. Ann Daly (Newcastle University, UK) discussed idiosyncratic toxicities that arise from genetically determined alterations in drug metabolism, highlighting the examples of diclofenac and isoniazid, both common causes of drug induced-liver injury in humans, which are believed to undergo metabolism to toxic reactive intermediates. There is increasing evidence that genotype for UGT2B7 and ABCC2 are relevant to the risk of toxicity with diclofenac and NAT2 to isoniazid-related liver injury due to functionally significant polymorphisms in these genes affecting the level of reactive intermediates formed.