A comprehensive evaluation of anti-diabetic drugs on nuclear receptor PXR platform.
Pregnane & Xenobiotic Receptor (PXR), one of the members of nuclear receptor superfamily, acts as a 'master-regulator' of drug metabolism and disposition machinery (DMD). Activation of PXR enables detoxification and elimination of toxic xenobiotics/endobiotics, and defends our body against chemical insults. On the contrary, PXR activation also imposes a serious concern for drug-drug interactions (DDIs). Such DDIs could either decrease the efficacy or lead to accumulation of co-administered drugs at toxic level. Therefore, it is desirable that during drug development process the small drug molecules are screened on PXR-platform prior to their clinical trial and prevent late stage failures. In view of this, we have selected a group of anti-diabetic drug molecules to examine if the success and potential failure of small molecule modulators can be pre-assessed and judiciously correlated on PXR platform. For this purpose, we have examined the PXR activation potential of the selected anti-diabetic drugs. Subsequent to screening of these anti-diabetic drugs, we elaborated the study further with rosiglitazone and pioglitazone (thiazolidinediones, TZDs) which are oral anti-diabetic formulations and have been in controversy owing to their association with cardiotoxicity and bladder cancer respectively. Our study revealed that some of the selected anti-diabetic drugs possess PXR activation potential, implying that these can up-regulate the expression of CYP3A4, UGT1A1, MDR1 and thereby can be predicted to inflict undesirable consequences.
['Singh|Shashi Kala|SK|', 'Yende|Ashutosh S|AS|', 'Ponnusamy|Kalaiarasan|K|', 'Tyagi|Rakesh K|RK|']
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 D000818:Animals D002460:Cell Line D002522:Chlorocebus aethiops D051544:Cytochrome P-450 CYP3A D004347:Drug Interactions D014453:Glucuronosyltransferase D006801:Humans D007004:Hypoglycemic Agents D000077205:Pioglitazone D000077297:Pregnane X Receptor D034741:RNA, Small Interfering D000077154:Rosiglitazone
Anti-diabetic drugs Small molecules Drug screening Promoter-reporter Stable cell line