Sample-to-sample comparison including in vivo samples seems to be is a potent tool to further explore in vitro data experiment. Identification step suggested that these two metabolites could correspond to 7-OH-N-desalkylquetiapine and quetiapine glucuronide, respectively. The minimum cluster size was set to 1. In addition, a potent competitive inhibitor of CYP2D6 is quinidine38,39,40,41. PLoS Comput. 2005, 20: 119-120. Source parameters were as follows: source voltage+3.0 and 4.0kV, sheath gas flow 60 units, auxiliary gas flow 10 units, capillary temperature 320C, S-Lens RF level 60 units. Biotechnol. Quetiapine is an antipsychotic that has rarely been linked to acute liver injury. Velayudhan L, Kirchner V: Quetiapine-induced myoclonus. The major metabolic pathways are sulfoxidati on to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. Google Scholar. & Taylor, D. M. Plasma concentrations of quetiapine, N-desalkylquetiapine, O-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide in relation to quetiapine dose, formulation, and other factors. Anal. PubMed Cardiovascular and respiratory system examinations were unremarkable. 4. Biotechnol. Bakken, G. V., Molden, E., Knutsen, K., Lunder, N. & Hermann, M. Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro. Differentiated HepaRG were incubated with quetiapine (13M) during H24 with or without cytochrome inhibitors. The existence of an abundant literature allows us to compare it with our data in order to assess their relevance3,4,5,6,7. Ion precursor selection was performed in the data dependent mode of operation where the most intense ion from the previous scan was selected for fragmentation. The use of newer drugs and medications with previously unknown hepatotoxicity add to the challenges faced by treating physicians. Same methodology was applied to other nodes, allowing identification of all the quetiapine-containing cluster molecules shown in Fig. CAS Kittler, K., Fessard, V., Maul, R. & Hurtaud-Pessel, D. CYP3A4 activity reduces the cytotoxic effects of okadaic acid in HepaRG cells. Dispos. We demonstrated that organizing data by their spectral similarities is a useful means to identifying new metabolites. (2014) and Ferron et al. Thus, pHH model may be limited by the lack of this cytochrome expression in a donor. 3). Integration of molecular networking and in-silico MS/MS fragmentation for natural products dereplication. Exp. Quetiapine: 7 things you should know - Drugs.com Google Scholar. In the present work we describe a case of fulminant hepatic failure secondary to use of quetiapine. Comparing HepaRG data with in vivo data appears critical to establish the proof of concept concerning the use of molecular network in in vitro drug metabolism exploration. Psychotropic drugs and liver disease: A critical review of https://doi.org/10.1038/s41598-020-77106-x, DOI: https://doi.org/10.1038/s41598-020-77106-x. PubMed Manier, S. K., Wagmann, L., Flockerzi, V. & Meyer, M. R. Toxicometabolomics of the new psychoactive substances -PBP and -PEP studied in HepaRG cell incubates by means of untargeted metabolomics revealed unexpected amino acid adducts. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Dispos. 2011, 168: 212-213. Quetiapine (QP) is a second-generation short-acting antipsychotic drug extensively metabolized in the liver, producing pharmacologically inactive metabolites and leading to diminished bioavailability. Dispos. Aninat, C. et al. Shannon, P. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Trey C, Davidson LS: The management of fulminant hepatic failure. Quetiapine | Drugs | BNF | NICE Clin. Isomer differentiation using. To further investigate quetiapine metabolism pathways, we used quetiapine metabolism inhibitors. We found that both isomers presented m/z 158.12 and m/z 269.07 fragments, which could correspond to the same alkyl chain of quetiapine and an oxidized tricycle, respectively. Among them, CYP3A4 and CYP2D6 are the predominant metabolic systems : CYP3A4 is known to give rise to N-desalkylquetiapine, N-desalkylquetiapine sulfoxide and quetiapine sulfoxide and CYP2D6 is known to give rise to 7-hydroxyquetiapine, 7-hydroxy-N-desalkylquetiapine3,6,7. Abe, S. et al. Information propagation within a molecular network consists in determining the structure of an unknown molecule using the structural information of the neighboring nodes. The hepatic and portal circulations were patent on Doppler examination. Pharmacol. 2005, 39: 1346-1348. Her symptoms were accompanied with nausea, vomiting, decrease appetite and abdominal pain for a few days duration. Metabolism inhibition visualization using MN brings further insight into metabolism pathways mapping and allows us to objectify a predominant CYP3A4/5 metabolism. 36, 4049 (2017). Biomed. Ketoconazole (10M) and quinidine (10M) were used as CYP3A4/5 and CYP2D6 inhibitors, respectively. J. Pharm. Risperdal and Seroquel can cause a blockage of the flow of bile from your liver (drug-induced cholestasis). Psychosomatics. In this quetiapine-containing cluster (Fig. Our data provide new evidences of the interest of molecular networking in drug metabolism exploration and allow our in vitro model consistency assessment. Periodic assessment of serum transaminases should be performed in patients with significant hepatic disease. (b) Details of the specific quetiapine-containing cluster. 1). After supernatant evaporation, the residue was dissolved in 200 L of LCMS grade water and transferred into chromatographic vials for LC-HR-MS analysis and quantification. Before using this medication, tell your doctor or pharmacist your medical history, especially of: eye cataracts, liver disease, . 5: in vitro versus in vivo quetiapine metabolism); https://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=8f00f95fd3ca4ea99fc6477ba1a55caf (Supplementary Fig. No risk factors or history suggestive of familial liver disease was provided. Indeed, this molecule undergoes an extensive and well-described metabolism. LC was performed on a on a Hypersil Gold column (5mm2.1mm, 3m) (Thermo Scientific, San Jose, CA). The molecular network was visualized using Cytoscape 3.5.1 software48. Article Int Clin Psychopharmacol. Viral serology test results for hepatitis A, B and C were negative. Forensic Toxicol. She was discharged home in a stable condition approximately six weeks after the initial admission on 20mg prednisolone per day with a suggested tapering of 5mg every week. Our patients case emphasizes the importance of keeping an open mind in cases of fulminant hepatic failure. Rep. 6, 625628 (1982). PDF Journal of Liver - Walsh Medical Media Differentiated HepaRG were incubated with quetiapine (13M) during different incubation time. PubMed Identifying the exact cause of hepatic failure and predicting prognosis is of paramount importance in managing such patients. 63, 214221 (2011). Full scan (MS1) data were acquired for each ionization mode at a resolution of 35,000 FWHM, with an AGC target of 1e6 and a maximum injection time of 120ms. Article A comparison of whole genome gene expression profiles of HepaRG cells and HepG2 cells to primary human hepatocytes and human liver tissues. Those tools combined with MN approaches provide a new way to integrate patient individual variability in therapeutic efficiency and toxicity studies. PubMed Article Gajwani P, Pozuelo L, Tesar GE: QT interval prolongation associated with quetiapine (Seroquel) overdose. Le Guillou, D. et al. This corroborate our quantitative results, showing a minor metabolism through CYP2D6 (Fig. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. 1a). Mullen J, Jibson MD, Sweitzer D: A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study. Figure2 displays the example of two m/z 400.168 isomers (RT 4.9 and 5.6min). No abnormality was detected on the neurological examination. All authors read and approved the final manuscript. A heated electrospray ionization source (HESI-II) was used for the ionization of the target compounds. quetiapine: Dosing, contraindications, side effects, and pill pictures Report of an international consensus meeting. mzCloudadvanced mass spectral database. Links between two nodes were only kept in the network if each node was in the top 10 most similar nodes. Quetiapine concentration was measured at H0, H3, H6, H8 and H24 using high-resolution liquid-chromatography and expressed relative to the value determined at H0 (set arbitrarily to 100%). Drug Information Handbook. Google Scholar. In view of the above-mentioned findings and her history, our patient was admitted with a probable diagnosis of quetiapine-induced hepatitis. Sharing and community curation of mass spectrometry data with global natural products social molecular networking. Similarly, production of some putative metabolites was decreased in the presence of quinidine (in red), suggesting a CYP2D6-dependent metabolic pathway (N-desalkyquetiapine sulfoxide and quetiapine M1). 8, 909920 (2012). https://doi.org/10.1007/s00204-020-02742-1 (2020). Drug Metab. Cytochrome inhibitors enable quetiapine metabolic pathway inhibition in differentiated HepaRG and primary Human hepatocytes (pHH). A vasculitic screen was performed, which revealed an anti-nuclear antibody titer of 1:1600 and positive anti-double-stranded deoxyribonucleic acid (dsDNA) results, but negative results for anti-liver kidney microsomal antibody. Samples were maintained at 15C in the autosampler and quality controls were injected before each analysis. Non-targeted screening LC-HRMS/MS method used for MN building was as follow: The mobile phases were composed of ammonium formiate at 2mM and formic acid 0.1% in water (phase A) and ammonium formiate at 2mM and formic acid 0.1% in methanol and acetonitrile (50/50) (phase B). Drug Monit. Her blood ethanol level was in the normal range. A 59-year-old Caucasian woman with known Parkinsons disease was being treated with quetiapine for hallucinations. Supplementary Table 2 reports putative identified compounds or metabolites contained in the quetiapine-containing clusters, and metabolic pathway involved in quetiapine metabolites biotransformation. Taken together, these results show that MN allows detailed visual analysis of in vitro metabolism, including metabolic pathways. Each incubation time is depicted in a specific color: H0 in white, H3 in green, H8 in yellow and H24 in orange. Day 4: 150 mg orally 2 times a day. Google Scholar. As drug-induced hepatotoxicity is the most common cause of fulminant hepatic failure in many parts of the world, consideration should be given to the medication(s) patients receive as being the potential cause, and a review of the list should be part of the clinical care administered. For those with impaired liver function, bile blockage can lead to more liver damage and blood toxicity. By allowing to propagate structural information within the network and facilitating sample-to-sample comparison, the MN approach offers valuable insights into drug metabolism9. https://doi.org/10.1002/dta.2550 (2018). 40, 509522 (2001). 10.1002/lt.500050102. El Hajj I, Sharara AI, Rockey DC: Subfulminant liver failure associated with quetiapine. OGrady JG, Alexander GJ, Hayllar KM, Williams R: Early indicators of prognosis in fulminant hepatic failure. (a) Blue box: 7-hydroxyquetiapine MS2 spectra shows the oxidized cycle structure without sulfur fragment (m/z 237.10). In particular, spectrally related molecules may display mass shifts corresponding to well-established biotransformation reactions (Supplementary Table 1)13. The detection of quetiapine and its metabolites was performed using this coculture model. Quetiapine was incubated in metabolically competent human liver cell models (HepaRG) for different times (0h, 3h, 8h, 24h) with or without cytochrom P450 (CYP) inhibitor (ketoconazole as CYP3A4/5 inhibitor and quinidine as CYP2D6 inhibitor), in order to study its metabolism kinetic and pathways.