Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo-Reference-Cited by-同舟云学术

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

Published:2022-01 Issue:1 Volume:23 Page:66-72
ISSN:1389-2002
Container-title:Current Drug Metabolism
language:en
Short-container-title:CDM

Author:

Smith Robert Løvsletten¹^ORCID,Wollmann Birgit M.²,Kausberg Marianne²,Mæland Sondre²,Tveito Marit³,O’Connell Kevin⁴^ORCID,Molden Espen⁵^ORCID,Kringen Marianne Kristiansen⁶^ORCID

Affiliation:

1. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway | NORMENT Center, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway

2. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway

3. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway | Norwegian National Advisory Unit on Aging and Health, Vestfold Hospital Trust, Tønsberg, Norway

4. NORMENT Center, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway

5. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway | Section for Pharmacology and Pharmaceutical Biosciences, Dep. of Pharmacy, University of Oslo, Oslo, Norway

6. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway | Department of Life Science and Health, OsloMet, Oslo Metropolitan University, Oslo, Norway

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.

Funder

South-Eastern Norway Regional Health Authority

European Union’s Horizon 2020 research and innovation program

Publisher

Bentham Science Publishers Ltd.

Subject

Clinical Biochemistry,Pharmacology

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