PMID- 33336382 OWN - NLM STAT- MEDLINE DCOM- 20210910 LR - 20211204 IS - 1532-6535 (Electronic) IS - 0009-9236 (Print) IS - 0009-9236 (Linking) VI - 109 IP - 6 DP - 2021 Jun TI - Metamizole is a Moderate Cytochrome P450 Inducer Via the Constitutive Androstane Receptor and a Weak Inhibitor of CYP1A2. PG - 1505-1516 LID - 10.1002/cpt.2141 [doi] AB - Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance. CI - (c) 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Bachmann, Fabio AU - Bachmann F AD - Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland. AD - Department of Biomedicine, University of Basel, Basel, Switzerland. FAU - Duthaler, Urs AU - Duthaler U AD - Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland. AD - Department of Biomedicine, University of Basel, Basel, Switzerland. FAU - Meyer Zu Schwabedissen, Henriette E AU - Meyer Zu Schwabedissen HE AD - Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. FAU - Puchkov, Maxim AU - Puchkov M AD - Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. FAU - Huwyler, Jorg AU - Huwyler J AD - Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. FAU - Haschke, Manuel AU - Haschke M AD - Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. AD - Institute of Pharmacology, University of Bern, Bern, Switzerland. FAU - Krahenbuhl, Stephan AU - Krahenbuhl S AD - Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland. AD - Department of Biomedicine, University of Basel, Basel, Switzerland. LA - eng GR - SNF 31003A_156270/SNSF_/Swiss National Science Foundation/Switzerland GR - SNF 31003A_156270/SNSF_/Swiss National Science Foundation/Switzerland PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210119 PL - United States TA - Clin Pharmacol Ther JT - Clinical pharmacology and therapeutics JID - 0372741 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Constitutive Androstane Receptor) RN - 0 (Cytochrome P-450 CYP1A2 Inhibitors) RN - 0 (Cytochrome P-450 Enzyme Inducers) RN - 0 (Pregnane X Receptor) RN - 0 (Receptors, Cytoplasmic and Nuclear) RN - 6429L0L52Y (Dipyrone) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.13.- (CYP2C9 protein, human) RN - EC 1.14.13.- (Cytochrome P-450 CYP2C9) RN - EC 1.14.14.1 (CYP1A2 protein, human) RN - EC 1.14.14.1 (CYP2B6 protein, human) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A2) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2B6) SB - IM CIN - Clin Pharmacol Ther. 2021 Jun;109(6):1373-1375. PMID: 34038591 MH - Adult MH - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology MH - Area Under Curve MH - Cell Line MH - Constitutive Androstane Receptor MH - Cytochrome P-450 CYP1A2/*genetics MH - Cytochrome P-450 CYP1A2 Inhibitors/*pharmacology MH - Cytochrome P-450 CYP2B6/biosynthesis/genetics MH - Cytochrome P-450 CYP2C9/biosynthesis/genetics MH - Cytochrome P-450 Enzyme Inducers/*pharmacology MH - Cytochrome P-450 Enzyme System/*biosynthesis/genetics MH - Dipyrone/*pharmacology MH - Drug Interactions MH - Enzyme Induction/*drug effects MH - Female MH - Genotype MH - Healthy Volunteers MH - Humans MH - Male MH - Pregnane X Receptor/antagonists & inhibitors/genetics MH - Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors/genetics MH - Young Adult PMC - PMC8247900 COIS- S.K. gave talks in symposia sponsored by Sanofi. All other authors declared no competing interests for this work. EDAT- 2020/12/19 06:00 MHDA- 2021/09/11 06:00 PMCR- 2021/01/19 CRDT- 2020/12/18 05:56 PHST- 2020/08/21 00:00 [received] PHST- 2020/11/07 00:00 [accepted] PHST- 2020/12/19 06:00 [pubmed] PHST- 2021/09/11 06:00 [medline] PHST- 2020/12/18 05:56 [entrez] PHST- 2021/01/19 00:00 [pmc-release] AID - CPT2141 [pii] AID - 10.1002/cpt.2141 [doi] PST - ppublish SO - Clin Pharmacol Ther. 2021 Jun;109(6):1505-1516. doi: 10.1002/cpt.2141. Epub 2021 Jan 19.