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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo

Author(s): Robert Løvsletten Smith*, Birgit M. Wollmann, Marianne Kausberg, Sondre Mæland, Marit Tveito, Kevin O’Connell, Espen Molden and Marianne Kristiansen Kringen

Volume 23, Issue 1, 2022

Published on: 16 February, 2022

Page: [66 - 72] Pages: 7

DOI: 10.2174/1389200223666220201152953

Price: $65

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Abstract

Background: Glucuronidation is an important metabolic pathway of clozapine (CLZ), but the impact of various uridine 5'diphospho-glucuronosyltransferases (UGT) polymorphisms on the exposure and metabolism of CLZ in vivo is unclear.

Objective: The objective of this study was to investigate the impact of UGT2B haplotype and UGT1A4*3 allele variants on the formation of CLZ glucuronide metabolites (5N- and N+-glucuronide) and CLZ exposure in patients’ serum after adjusting for sex, age, and smoking habits.

Methods: The study was based on serum samples from CLZ-treated patients (n=79) subjected to routine therapeutic drug monitoring (TDM) at Diakonhjemmet Hospital, Oslo, Norway. From the same patients, the following UGT variants were genotyped using Real-Time PCR: UGT2B:GA haplotype (defined as UGT2B:GA; rs1513559A>G and rs416593T>A) and UGT1A4*3 (rs2011425T>G). Serum concentrations of CLZ 5N- and N+-glucuronide were measured by UPLC high-resolution mass spectrometry.

Results: None of the genotypes had significant impact on CLZ exposure (p>0.05). However, compared to UGT2B:AT/AT and UGT1A4*1/*1, the 5N-glucuronide exposure was reduced in UGT2B:GA/GA carriers (-75 %, p=0.03) while the exposure was non-significantly increased in UGT1A4*3 carriers (+100 %, p=0.14), respectively. The N+-glucuronide exposure was unchanged in UGT1A4*3 vs. noncarriers (p=0.28), but significantly reduced in heterozygous (-50 %, p=0.016) and homozygous carriers (-70 %, p=0.021) of UGT2B:GA compared to UGT2B:AT/AT carriers, respectively.

Conclusion: The UGT2B:GA and UGT1A4*3 variants had no impact on CLZ exposure but were associated with differences and preferences in CLZ glucuronidation. The latter might be of potential relevance for CLZ tolerability since levels of the N+-glucuronide metabolite may reflect the generation and trapping of reactive metabolites involved in CLZ-induced toxicity.

Keywords: Clozapine, uridine 5'-diphospho-glucuronosyltransferase, therapeutic drug monitoring, glucuronidation, metabolism, highresolution mass spectrometry.

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[1]
Leucht, S.; Cipriani, A.; Spineli, L.; Mavridis, D.; Orey, D.; Richter, F.; Samara, M.; Barbui, C.; Engel, R.R.; Geddes, J.R.; Kissling, W.; Stapf, M.P.; Lässig, B.; Salanti, G.; Davis, J.M. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet, 2013, 382(9896), 951-962.
[http://dx.doi.org/10.1016/S0140-6736(13)60733-3] [PMID: 23810019]
[2]
Gerson, S.L.; Meltzer, H. Mechanisms of clozapine-induced agranulocytosis. Drug Saf., 1992, 7(Suppl. 1), 17-25.
[http://dx.doi.org/10.2165/00002018-199200071-00007] [PMID: 1503673]
[3]
Wong, J.; Delva, N. Clozapine-induced seizures: Recognition and treatment. Can. J. Psychiatry, 2007, 52(7), 457-463.
[http://dx.doi.org/10.1177/070674370705200708] [PMID: 17688010]
[4]
Joober, R.; Boksa, P. Clozapine: A distinct, poorly understood and under-used molecule. J. Psychiatry Neurosci., 2010, 35(3), 147-149.
[http://dx.doi.org/10.1503/jpn.100055] [PMID: 20420765]
[5]
Hiemke, C.; Bergemann, N.; Clement, H. W.; Conca, A.; Deckert, J.; Domschke, K.; Eckermann, G.; Egberts, K.; Gerlach, M.; Greiner, C.; Grunder, G.; Haen, E.; Havemann-Reinecke, U.; Hefner, G.; Helmer, R.; Janssen, G.; Jaquenoud, E.; Laux, G.; Messer, T.; Mossner, R.; Muller, M. J.; Paulzen, M.; Pfuhlmann, B.; Riederer, P.; Saria, A.; Schoppek, B.; Schoretsanitis, G.; Schwarz, M.; Gracia, M. S.; Stegmann, B.; Steimer, W.; Stingl, J. C.; Uhr, M.; Ulrich, S.; Unterecker, S.; Waschgler, R.; Zernig, G.; Zurek, G.; Baumann, P. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry, 2018, 51(1-02), 9-62.
[6]
Dain, J.G.; Nicoletti, J.; Ballard, F. Biotransformation of clozapine in humans. Drug Metab. Dispos., 1997, 25(5), 603-609.
[PMID: 9152600]
[7]
Thorn, C.F.; Müller, D.J.; Altman, R.B.; Klein, T.E. PharmGKB summary: Clozapine pathway, pharmacokinetics. Pharmacogenet. Genomics, 2018, 28(9), 214-222.
[http://dx.doi.org/10.1097/FPC.0000000000000347] [PMID: 30134346]
[8]
van der Weide, J.; Steijns, L.S.; van Weelden, M.J. The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics, 2003, 13(3), 169-172.
[http://dx.doi.org/10.1097/00008571-200303000-00006] [PMID: 12618594]
[9]
Villard, P.H.; Herber, R.; Sérée, E.M.; Attolini, L.; Magdalou, J.; Lacarelle, B. Effect of cigarette smoke on UDP-glucuronosyltransferase activity and cytochrome P450 content in liver, lung and kidney microsomes in mice. Pharmacol. Toxicol., 1998, 82(2), 74-79.
[http://dx.doi.org/10.1111/j.1600-0773.1998.tb01401.x] [PMID: 9498235]
[10]
Smith, R.L.; O’Connell, K.; Athanasiu, L.; Djurovic, S.; Kringen, M.K.; Andreassen, O.A.; Molden, E. Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients-a genome-wide association study adjusting for smoking habits. Transl. Psychiatry, 2020, 10(1), 198.
[http://dx.doi.org/10.1038/s41398-020-00888-1] [PMID: 32555152]
[11]
Pardiñas, A.F.; Nalmpanti, M.; Pocklington, A.J.; Legge, S.E.; Medway, C.; King, A.; Jansen, J.; Helthuis, M.; Zammit, S.; MacCabe, J.; Owen, M.J.; O’Donovan, M.C.; Walters, J.T.R. Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism. Am. J. Psychiatry, 2019, 176(6), 477-486.
[http://dx.doi.org/10.1176/appi.ajp.2019.18050589] [PMID: 30922102]
[12]
Auton, A.; Brooks, L.D.; Durbin, R.M.; Garrison, E.P.; Kang, H.M.; Korbel, J.O.; Marchini, J.L.; McCarthy, S.; McVean, G.A.; Abecasis, G.R. 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature, 2015, 526(7571), 68-74.
[http://dx.doi.org/10.1038/nature15393] [PMID: 26432245]
[13]
Mijderwijk, H.; Klimek, M.; van Beek, S.; van Schaik, R.H.; Duivenvoorden, H.J.; Stolker, R.J. Implication of UGT2B15 genotype polymorphism on postoperative anxiety levels in patients receiving lorazepam premedication. Anesth. Analg., 2016, 123(5), 1109-1115.
[http://dx.doi.org/10.1213/ANE.0000000000001508] [PMID: 27622723]
[14]
Murphy, S.E.; von Weymarn, L.B.; Parenteau, M.; Stepanov, I.; Tiirikainen, M.; LeMarchand, L.; Park, S.L. Influence of UGT2B10 genotype on urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol- N-glucuronide by african american smokers. Chem. Res. Toxicol., 2018, 31(3), 168-175.
[http://dx.doi.org/10.1021/acs.chemrestox.7b00264] [PMID: 29460622]
[15]
Benoit-Biancamano, M.O.; Adam, J.P.; Bernard, O.; Court, M.H.; Leblanc, M.H.; Caron, P.; Guillemette, C. A pharmacogenetics study of the human glucuronosyltransferase UGT1A4. Pharmacogenet. Genomics, 2009, 19(12), 945-954.
[http://dx.doi.org/10.1097/FPC.0b013e3283331637] [PMID: 19890225]
[16]
Ehmer, U.; Vogel, A.; Schütte, J.K.; Krone, B.; Manns, M.P.; Strassburg, C.P. Variation of hepatic glucuronidation: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4. Hepatology, 2004, 39(4), 970-977.
[http://dx.doi.org/10.1002/hep.20131] [PMID: 15057901]
[17]
Erickson-Ridout, K.K.; Zhu, J.; Lazarus, P. Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants. Pharmacogenet. Genomics, 2011, 21(9), 539-551.
[http://dx.doi.org/10.1097/FPC.0b013e328348c76b] [PMID: 21750471]
[18]
Haslemo, T.; Loryan, I.; Ueda, N.; Mannheimer, B.; Bertilsson, L.; Ingelman-Sundberg, M.; Molden, E.; Eliasson, E. UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems. Clin. Pharmacol. Ther., 2012, 92(2), 221-227.
[http://dx.doi.org/10.1038/clpt.2012.46] [PMID: 22713701]
[19]
Erickson-Ridout, K.K.; Sun, D.; Lazarus, P. Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)7 TAA and UGT1A4 L48V polymorphisms. Pharmacogenet. Genomics, 2012, 22(8), 561-576.
[http://dx.doi.org/10.1097/FPC.0b013e328354026b] [PMID: 22565219]
[20]
Partridge, E.; Trobbiani, S.; Stockham, P.; Charlwood, C.; Kostakis, C. A case study involving u-47700, diclazepam and flubromazepam-application of retrospective analysis of HRMS data. J. Anal. Toxicol., 2018, 42(9), 655-660.
[http://dx.doi.org/10.1093/jat/bky039] [PMID: 29945197]
[21]
Ghotbi, R.; Mannheimer, B.; Aklillu, E.; Suda, A.; Bertilsson, L.; Eliasson, E.; Osby, U. Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure--an impact similar to male gender or smoking in schizophrenic patients. Eur. J. Clin. Pharmacol., 2010, 66(5), 465-474.
[http://dx.doi.org/10.1007/s00228-009-0783-8] [PMID: 20143052]
[22]
Machiela, M.J.; Chanock, S.J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics, 2015, 31(21), 3555-3557.
[http://dx.doi.org/10.1093/bioinformatics/btv402] [PMID: 26139635]
[23]
Stephens, M.; Smith, N.J.; Donnelly, P. A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet., 2001, 68(4), 978-989.
[http://dx.doi.org/10.1086/319501] [PMID: 11254454]
[24]
Ng, W.; Kennar, R.; Uetrecht, J. Effect of clozapine and olanzapine on neutrophil kinetics: Implications for drug-induced agranulocytosis. Chem. Res. Toxicol., 2014, 27(7), 1104-1108.
[http://dx.doi.org/10.1021/tx500183x] [PMID: 24968069]
[25]
Smith, R.L.; Kyllesø, L.; Haslemo, T.; Andreassen, O.A.; Molden, E. Reduction in N-desmethylclozapine level is determined by daily dose but not serum concentration of valproic acid-indications of a presystemic interaction mechanism. Ther. Drug Monit., 2019, 41(4), 503-508.
[http://dx.doi.org/10.1097/FTD.0000000000000619] [PMID: 31259880]

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