Cristin-resultat-ID: 1998434
Sist endret: 20. februar 2023, 18:39
NVI-rapporteringsår: 2022
Resultat
Vitenskapelig artikkel
2022

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

Bidragsytere:
  • Robert Løvsletten Smith
  • Birgit Malene Tovik Wollmann
  • Marianne Kausberg
  • Sondre Mæland
  • Marit Tveito
  • Kevin Sean O'Connell
  • mfl.

Tidsskrift

Current drug metabolism
ISSN 1389-2002
e-ISSN 1875-5453
NVI-nivå 1

Om resultatet

Vitenskapelig artikkel
Publiseringsår: 2022
Publisert online: 2022
Trykket: 2022
Volum: 23
Hefte: 1
Sider: 66 - 72
Open Access

Importkilder

Scopus-ID: 2-s2.0-85130855261

Beskrivelse Beskrivelse

Tittel

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

Sammendrag

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

Bidragsytere

Robert Løvsletten Smith

  • Tilknyttet:
    Forfatter
    ved Psykoseforskning, seksjon (NORMENT/KG Jebsen OUS) ved Oslo universitetssykehus HF
  • Tilknyttet:
    Forfatter
    ved Senter for presisjonspsykiatri ved Universitetet i Oslo
  • Tilknyttet:
    Forfatter
    ved Senter for Psykofarmakologi ved Diakonhjemmet sykehus

Birgit Malene Tovik Wollmann

  • Tilknyttet:
    Forfatter
    ved Senter for Psykofarmakologi ved Diakonhjemmet sykehus

Marianne Kausberg

  • Tilknyttet:
    Forfatter
    ved Senter for Psykofarmakologi ved Diakonhjemmet sykehus

Sondre Mæland

  • Tilknyttet:
    Forfatter

Marit Tveito

  • Tilknyttet:
    Forfatter
    ved Nasjonalt senter for aldring og helse ved Sykehuset i Vestfold HF
  • Tilknyttet:
    Forfatter
    ved Senter for Psykofarmakologi ved Diakonhjemmet sykehus
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