Pregnane X Receptor: Prediction and Attenuation of Human CYP3A4 Enzyme Induction and Drug–Drug Interactions

2008 ◽  
pp. 405-418 ◽  
Author(s):  
Michael W. Sinz
Keyword(s):  
Drug Interactions ◽  
Enzyme Induction ◽  
Pregnane X Receptor ◽  
Cyp3a4 Enzyme

Stress-drug interactions: Evidence for rapid enzyme induction

Life Sciences ◽  
1965 ◽  
Vol 4 (15) ◽  
pp. 1449-1454 ◽  
Author(s):  
C.W. Driever ◽  
W.F. Bousquet
Keyword(s):  
Drug Interactions ◽  
Enzyme Induction

scholarly journals Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

2012 ◽  
Vol 216 (3) ◽  
pp. 297-305 ◽  
Author(s):  
Akira Takeshita ◽  
Junko Igarashi-Migitaka ◽  
Noriyuki Koibuchi ◽  
Yasuhiro Takeuchi
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Drug Interactions ◽  
Luciferase Reporter ◽  
Pcr Analysis ◽  
Metabolic Clearance ◽  
Mrna Levels ◽  
Steroid And Xenobiotic Receptor ◽  
Cyp3a4 Enzyme ◽  
Xenobiotic Receptor

Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor prognosis. Mitotane alone or in combination with other cytotoxic drugs is a common therapeutic option for ACC. In addition to its adrenolytic function, mitotane has been known for decades to increase the metabolic clearance of glucocorticoids. It was recently shown that the tyrosine kinase inhibitor sunitinib is also rapidly metabolized in patients treated with mitotane, indicating that mitotane engages in clinically relevant drug interactions. Although the precise mechanism of these interactions is not well understood, cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is a key enzyme to inactivate both glucocorticoids and sunitinib. The nuclear receptor steroid and xenobiotic receptor (SXR (NR1I2)) is one of the key transcriptional regulators ofCYP3A4gene expression in the liver and intestine. A variety of xenobiotics bind to SXR and stimulate transcription of xenobiotic-response elements (XREs) located in theCYP3A4gene promoter. In this study, we evaluated the effects of mitotane on SXR-mediated transcriptionin vitroby luciferase reporter analysis, SXR–steroid receptor coactivator 1 (SRC1) interactions, quantitative real-time PCR analysis ofCYP3A4expression, SXR knockdown, and CYP3A4 enzyme activity assays using human hepatocyte-derived cells. We found that mitotane activated SXR-mediated transcription of the XREs. Mitotane recruited SRC1 to the ligand-binding domain of SXR. Mitotane increasedCYP3A4mRNA levels, which was attenuated by SXR knockdown. Finally, we showed that mitotane increased CYP3A4 enzyme activity. We conclude that mitotane can induceCYP3A4gene expression and suggest that mitotane is used cautiously due to its drug–drug interactions.

scholarly journals Screening Ingredients from Herbs against Pregnane X Receptor in the Study of Inductive Herb-Drug Interactions: Combining Pharmacophore and Docking-Based Rank Aggregation

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Zhijie Cui ◽  
Hong Kang ◽  
Kailin Tang ◽  
Qi Liu ◽  
Zhiwei Cao ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Target Genes ◽  
Pharmacophore Model ◽  
Pregnane X Receptor ◽  
Rank Aggregation ◽  
Pharmacophore Modelling ◽  
Interaction Database ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme

The issue of herb-drug interactions has been widely reported. Herbal ingredients can activate nuclear receptors and further induce the gene expression alteration of drug-metabolizing enzyme and/or transporter. Therefore, the herb-drug interaction will happen when the herbs and drugs are coadministered. This kind of interaction is called inductive herb-drug interactions. Pregnane X Receptor (PXR) and drug-metabolizing target genes are involved in most of inductive herb-drug interactions. To predict this kind of herb-drug interaction, the protocol could be simplified to only screen agonists of PXR from herbs because the relations of drugs with their metabolizing enzymes are well studied. Here, a combinational in silico strategy of pharmacophore modelling and docking-based rank aggregation (DRA) was employed to identify PXR’s agonists. Firstly, 305 ingredients were screened out from 820 ingredients as candidate agonists of PXR with our pharmacophore model. Secondly, DRA was used to rerank the result of pharmacophore filtering. To validate our prediction, a curated herb-drug interaction database was built, which recorded 380 herb-drug interactions. Finally, among the top 10 herb ingredients from the ranking list, 6 ingredients were reported to involve in herb-drug interactions. The accuracy of our method is higher than other traditional methods. The strategy could be extended to studies on other inductive herb-drug interactions.

The Pregnane X Receptor Gene-Humanized Mouse: A Model for Investigating Drug-Drug Interactions Mediated by Cytochromes P450 3A

2006 ◽  
Vol 35 (2) ◽  
pp. 194-200 ◽  
Author(s):  
Xiaochao Ma ◽  
Yatrik Shah ◽  
Connie Cheung ◽  
Grace L. Guo ◽  
Lionel Feigenbaum ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Cytochromes P450 ◽  
Receptor Gene ◽  
Pregnane X Receptor ◽  
Humanized Mouse

scholarly journals Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor

2014 ◽  
Vol 59 (1) ◽  
pp. 96-104 ◽  
Author(s):  
Rita Piedade ◽  
Stefanie Traub ◽  
Andreas Bitter ◽  
Andreas K. Nüssler ◽  
José P. Gil ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Antimalarial Drug ◽  
Pregnane X Receptor ◽  
Antimalarial Drugs ◽  
Drug Metabolites ◽  
Protein Levels ◽  
Two Hybrid ◽  
Pharmacokinetic Drug

ABSTRACTMalaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether thesein vitrofindings are ofin vivorelevance has to be addressed in future clinical drug-drug interaction studies.

scholarly journals In Silico Prediction and Pharmacokinetic Comparison of Ursodeoxycholic Acid and Obeticholic Acid in the Management of Primary Biliary Cholangitis

2021 ◽  
Vol 11 (2-S) ◽  
pp. 113-117
Author(s):  
Manali Sudhir Dhage ◽  
Nila Ganamurali ◽  
Dhivya Dhanasekaran ◽  
Sarvesh Sabarathinam
Keyword(s):  
Drug Interactions ◽  
Ursodeoxycholic Acid ◽  
In Silico ◽  
Software Tool ◽  
Pharmacokinetic Profile ◽  
Primary Biliary Cholangitis ◽  
Obeticholic Acid ◽  
Acid Therapy ◽  
Concurrent Use ◽  
Cyp3a4 Enzyme

Background: Primary Biliary Cholangitis (PBC) is a persistent liver disease. Ursodeoxycholic acid is used as a first-line treatment for the past two decades. However, concurrent use of Ursodeoxycholic acid reported with a severe adverse drug reaction. Obeticholic acid has been started utilizing as monotherapy and also with Ursodeoxycholic acid in a patient who is intolerant to Ursodeoxycholic acid therapy. We primarily aimed to compare the pharmacokinetic & toxicity profiles of Ursodeoxycholic acid and Obeticholic acid using in silico methods. Method: The pharmacokinetic profile of UDCA & OCA was observed from PKCSM server online database, OSIRIS® property Explorer, T.E.S.T. (Toxicity estimation software tool) & Molinspiration® is used to estimate the drug toxicity profiles. Result: This computer-aided response provides a great understanding and creates a gap between the theoretical and clinical evidence for UDCA & OCA's preference in PBC management. Conclusion: Co-administration of Obeticholic acid with Ursodeoxycholic acid will be an effective treatment for PBC in patients with UDCA intolerants. However, both medications are well-recognized substrates of the CYP3A4 enzyme and may lead to unintended drug interactions and side effects. Keywords: Primary Biliary Cholangitis, Obeticholic acid, Ursodeoxycholic acid, CYP3A4, Drug Interactions, Pharmacokinetics.

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