Evidence-based drug repositioning and target discovery

Abstract

FAERS is a public database that accumulates more than 9 million self-reports of adverse events. In nearly half of the cases, multiple drugs are prescribed, so that potential drug-drug interactions are to be analyzed. Focusing on adverse reactions relating to diabetes mellitus (DM) caused by an anti-schizophrenic quetiapine, we found that concomitant use of vitamin D analogs significantly suppresses the occurrence of quetiapine-induced DM in FAERS. Experimental validation revealed that quetiapine acutely caused insulin resistance, which was mitigated by dietary supplementation with cholecalciferol. In an expression database, several genes downstream of insulin receptor were downregulated by quetiapine. Further experiments clarified that a PI3K regulatory protein gene, pik3r1, was downregulated by quetiapine, which was reversed by cholecalciferol in mouse skeletal muscle. In addition, insulin-stimulated glucose uptake into cultured myotubes was inhibited by quetiapine, which was reversed by pretreatment with calcitriol. These results suggest that vitamin D prevents the atypical antipsychotic-induced hyperglycemia and insulin resistance by upregulation of PI3KR1. Until now, we have obtained several combinations of concomitant medications to reduce specific adverse events by FAERS analysis. This new strategy will pave the way for drug repositioning and clarifying unknown disease mechanisms.