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18 Abstracts / Toxicology

12-2valuation and adverse consequences of metabolicioactivation

evin Park

Univeristy of Liverpool, United Kingdom

Adverse drug reactions (ADRs) are a major complication of drugherapy and drug development. The formation of chemically reac-ive metabolites has been implicated in a number of off-targetincluding idiosyncratic) ADRs. Studies with model compoundsrugs such as acetaminophen have defined the response of tar-et organs to drug bioactivation with respect to various biologicalutcomes which include adaptation, apoptosis, necrosis inflamma-ion and activation of the innate and adaptive immune systems.

number of idiosyncratic ADRs have the clinical hallmarks ofhypersensitivity reaction and may affect various systems. The

ear of such reactions is a major contribution to drug attrition.t present there are no accepted methods for the identification ofrugs which may cause idiosyncratic drug. The first step towardsuch methodology has been the development of screens for “chemi-ally reactive” metabolites. The chemical basis of drug bioactivationan usually be rationalised and synthetic strategies put in placeo prevent such bioactivation. However, there is no simple cor-elation between drug bioactivation “in vitro” and ADRs. Such ahemical approach is clearly limited by the facts that (a) not allrugs that can undergo bioactivation by human drug-metabolisingnzymes are associated with hypersensitivity in the clinic and (b)rug bioactivation may not always be a mandatory step in drugypersensitivity. To predict such reactions require an integratednderstanding of the chemical, immunological and genetic basis ofDRs and the development of novel biomarkers which can be used

o bridge between the clinic and novel in vitro model systems.

oi:10.1016/j.toxlet.2012.03.082

12-3rug interactions with hepatocellular transport systems andcquired forms of liver disease

runo Stieger

University Hospital, Zurich, Switzerland

Bile formation and elimination of metabolic end products orenobiotics are key functions of the liver. Bile salts are a mainomponent of bile and are concentrated several hundred-fold fromhe portal blood plasma to bile. This is achieved by the polar dis-ribution of transporters mediating uptake of bile salts form theortal blood plasma into hepatocytes and exporting bile salt acrosshe canalicular plasma membrane. Uptake is mediated predomi-antly in a sodium-dependent manner by the sodium-taurocholateotransporting polypeptide (NTCP) and to a minor extent by organicnion transporting polypeptides (OATPs). OATPs are also uptakeystems for drugs into hepatocytes. Export of bile salts across theanalicular membrane is mediated by the bile salt export pumpSEP. Drugs can interact at the hepatocellular uptake site e.g. atATPs. This will usually lead to pharmacokinetic interactions with

ncreased plasma levels of drugs and followed possibly by sys-emic adverse drug events. Within hepatocytes, drugs or their

etabolites can directly or indirectly inhibit BSEP. This will lead

o an accumulation of potentially cytotoxic bile salts within hep-tocytes. If BSEP inhibition persists, the elevated bile salts willamage hepatocytes and lead to liver disease, i.e. acquired intra-

s 211S (2012) S4–S23

hepatic cholestasis. Using BSEP expressed in membrane vesicles,investigation of a large number of drugs for their potential to inhibitBSEP has demonstrated a correlation of the affinity of the drugs asinhibitors of BSEP with clinical incidences of liver disease caused bysuch drugs. While this system has been worked out in detail, less isknown about susceptibility factors. Individual patients can be put atrisk for drug induced liver injury by variants of drug uptake systems,variations in drug metabolism or by variants of BSEP. The p.V44Avariant of BSEP has been demonstrated to constitute a suscepti-bility factor for acquired cholestasis. The role of genetic variantsof drug uptake systems is at the moment less well understood. Inaddition, in vitro evidence shows for example that the transportactivity of OATPs can be modulated by endogenous substances orselected drugs. Hence, susceptibility to drug induced cholestasisdue to BSEP inhibition is complex and may involve BSEP, as well asdrug uptake systems and/or drug metabolism.

doi:10.1016/j.toxlet.2012.03.083

S12-5In vivo imaging of hepatic steatosis

Hans-Paul Juretschke

Sanofi-Aventis Deutschland GmbH, Germany

Lipids play a major physiological role and the liver is the keyorgan in their metabolism. Hepatic synthesis of fatty acids and oflipoproteins influences lipid circulation, while accumulation withinthe hepatocytes of lipid droplets due to a variety of metabolic alter-ations results in steatosis or even steatohepatitis. Hepatic steatosisis the most prevalent liver disorder in the developed world andclosely related to the metabolic syndrome, to insulin resistance andto obesity. Steatosis can also be induced by drugs.

Traditionally, hepatic fat is assessed by liver biopsy, the goldstandard so far, although its drawbacks are evident: non-targeted,invasive, and difficult to repeat.

Emerging imaging techniques, especially magnetic resonanceimaging and proton magnetic resonance spectroscopy, allow anon-invasive, repetitive monitoring and quantification of hepaticlipid content. The non-destructive nature of these modalities pro-vides the additional option for correlation with other physiologicalparameters or biomarkers.

None of these newer techniques is however able, so far, to dif-ferentiate micro- and macrovesicular steatosis.

doi:10.1016/j.toxlet.2012.03.084

S13Clinical toxicology: Are new insights into epidemiology andmechanisms of toxicity changing our approach to importantpoisonings?

S13-1Analgesics toxicity: The banning of Dextropropoxyphene inEurope

D. Nicholas Bateman, United Kingdom

NPIS Edinburgh, United Kingdom

Purpose: Dextropropoxyphene (DXP) was first marketed in the1960s, alone and in combination with paracetamol (PARA). This