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Preventing clinical drug-induced liver injury (DILI) remains a major challenge, because DILI develops via multifactorial mechanisms. Immune and inflammatory reactions are considered important mechanisms of DILI; however, biomarkers from in vitro systems using immune cells have not been comprehensively studied. The aims of this study were (1) to identify promising biomarker genes for predicting DILI in an in vitro coculture model of peripheral blood mononuclear cells (PBMCs) with a human liver cell line, and (2) to evaluate these genes as predictors of DILI using a panel of drugs with different clinical DILI risk. Transcriptome-wide analysis of PBMCs cocultured with HepG2 or differentiated HepaRG cells that were treated with several drugs revealed an appropriate separation of DILI-positive and DILI-negative drugs, from which 12 putative biomarker genes were selected. To evaluate the predictive performance of these genes, PBMCs cocultured with HepG2 cells were exposed to 77 different drugs, and gene expression levels in PBMCs were determined. The MET proto-oncogene receptor tyrosine kinase (MET) showed the highest area under the receiver-operating characteristic curve (AUC) value of 0.81 among the 12 genes with a high sensitivity/specificity (85/66%). However, a stepwise logistic regression model using the 12 identified genes showed the highest AUC value of 0.94 with a high sensitivity/specificity (93/86%). Taken together, we established a coculture system using PBMCs and HepG2 cells and selected biomarkers that can predict DILI risk. The established model would be useful in detecting the DILI potential of compounds, in particular those that involve an immune mechanism.

Objectives To examine the effect of combining a nonselective muscarinic receptor antagonist, 5‐hydroxymethyl tolterodine (an active metabolite of fesoterodine), with a β3 adrenoceptor agonist, mirabegron, in a rat model of pelvic congestion. Methods The rat pelvic congestion model used female Sprague‐Dawley rats with their bilateral common iliac and uterine veins ligated. Expressions of M2 and M3 receptor subtypes in the urothelium and detrusor were detected by real‐time polymerase chain reaction assays. The effects of both drugs were investigated on isolated bladder strips contracted by electrical field stimulation. in vivo single cystometry was used to assess the effects of 5‐hydroxymethyl tolterodine and mirabegron independently or in combination on bladder capacity, micturition pressure, and threshold pressure. Results Pelvic congestion rats showed decreased bladder capacity compared with controls, but micturition pressure and threshold pressure were unchanged. Pelvic congestion model rats also demonstrated an approximately two‐fold increase in expression of both M2 and M3 receptor subtypes in the urothelium. Additive relaxant effects of 5‐hydroxymethyl tolterodine and mirabegron were observed in vitro in the electrical field stimulation‐induced contractions of bladder strips from pelvic congestion rats. In vivo, bladder capacity was increased significantly by a combination of 5‐hydroxymethyl tolterodine and mirabegron, with the combined effect exceeding the sum of the effects of monotherapies. Micturition pressure and threshold pressure did not significantly differ between groups. Conclusions The combination of 5‐hydroxymethyl tolterodine with mirabegron suggests the potential of synergistic effects in a rat pelvic congestion model.

In this survey, the correlation between adverse drug reactions (ADRs) in human and animal toxicities was investigated for 393 medicines which were approved in Japan from September 1999 to March 2013. ADRs were collected from each Japanese package insert. Comparable animal toxicities with ADRs were collected by thorough investigation of common technical documents. The results of this survey show that hypertension and/or hypotension were mainly observed in medicines affecting the central nervous system. Hypertension was also observed in antipyretics, analgesics, anti-inflammatory agents, vasoconstrictors and agents using antibody. Concordance between human ADRs and animal toxicities was analysed. True-positive rate for hypertension and hypotension is 0.29 and 0.52, respectively. Positive likelihood ratio and inverse negative likelihood ratio are 1.98 and 1.21, respectively, in hypertension and 1.67 and 1.44, respectively, in hypotension. Concordance between human ADRs and animal toxicities is not so high in hypertension and hypotension. Identified mechanisms as on-target for hypertension and hypotension are 29.8% and 30.5%, respectively. More than half of the causative factors of hypertension and hypotension were unable to be elucidated. Our results show that the intake of medicines is often linked to blood pressure variations that are not predicted in animal toxicity studies. Improvement of drug development processes may be necessary to provide safer medicines because current animal toxicity studies are insufficient to predict all ADRs in human beings.