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dc.contributor.authorKeating, Christopher
dc.contributor.authorEwart, Lornal
dc.contributor.authorGibbons, Stephen
dc.contributor.authorGrundy, Luke
dc.contributor.authorValentin, Jean-Pierre
dc.contributor.authorGrundy, David
dc.identifier.citationKeating , C , Ewart , L , Gibbons , S , Grundy , L , Valentin , J-P & Grundy , D 2010 , ' The validation of an invitro colonic motility assay as a biomarker for gastrointestinal adverse drug reactions ' , Toxicology and Applied Pharmacology , vol. 245 , no. 3 , pp. 299-309 .
dc.identifier.otherPURE: 2076493
dc.identifier.otherPURE UUID: 0270a327-40c2-4a1b-b5c2-81efb6b711f1
dc.identifier.otherScopus: 77952953522
dc.description.abstractMotility-related gastrointestinal adverse drug reactions (GADRs), such as constipation and diarrhea, are some of the most frequently reported adverse events associated with the clinical development of new chemical entities, and for marketed drugs. However, biomarkers capable of detecting such GADRs are lacking. Here, we describe an in vitro assay developed to detect and quantify changes in intestinal motility as a surrogate biomarker for constipation/diarrhea-type GADRs. In vitro recordings of intraluminal pressure were used to monitor the presence of colonic peristaltic motor complexes (CPMCs) in mouse colonic segments. CPMC frequency, contractile and total mechanical activity were assessed. To validate the assay, two experimental protocols were conducted. Initially, five drugs with known gastrointestinal effects were tested to determine optimal parameters describing excitation and inhibition as markers for disturbances in colonic motility. This was followed by a “blinded” evaluation of nine drugs associated with or without clinically identified constipation/diarrhea-type GADRs. Concentration–response relationships were determined for these drugs and the effects were compared with their maximal free therapeutic plasma concentration in humans. The assay detected stimulatory and inhibitory responses, likely correlating to the occurrence of diarrhea or constipation. Concentration-related effects were identified and potential mechanisms of action were inferred for several drugs. Based on the results from the fourteen drugs asssessed, the sensitivity of the assay was calculated at 90%, with a specificity of 75% and predictive capacity of 86%. These results support the potential use of this assay in screening for motility-related GADRs during early discovery phase, safety pharmacology assessmenten
dc.relation.ispartofToxicology and Applied Pharmacology
dc.titleThe validation of an invitro colonic motility assay as a biomarker for gastrointestinal adverse drug reactionsen
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionHealth & Human Sciences Research Institute
dc.contributor.institutionDepartment of Human and Environmental Sciences
dc.contributor.institutionPharmacology and Clinical Science Research
dc.description.statusPeer reviewed
rioxxterms.typeJournal Article/Review

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