ArticlePharmacogenetics and genomics2012
Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)₇TAA and UGT1A4 L48V polymorphisms.
Article in Pharmacogenetics and genomics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 43 citations in OpenAlex.
- Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China.European journal of clinical pharmacology · 2014Trial
- Modulatory effects of valproic acid and UGT polymorphisms on norclozapine plasma levels in clozapine-treated patients with schizophrenia.Scientific reports · 2026Article
- Impact of the transcription factor nuclear factor 1 B T>C polymorphism on clozapine metabolism in vivo and expression of intestinal transporters in vitro.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Identification of key genes and pathways in schizophrenia: a bioinformatics analysis based on GWAS and GEO.Frontiers in psychiatry · 2025Article
- Predictors of clozapine concentration and psychiatric symptoms in patients with schizophrenia.PloS one · 2025Article
- Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: a longitudinal analysis and genome-wide association study using UK clinical monitoring data.The lancet. Psychiatry · 2023Article
- Hypogonadism in Women with Prader-Willi Syndrome-Clinical Recommendations Based on a Dutch Cohort Study, Review of the Literature and an International Expert Panel Discussion.Journal of clinical medicine · 2021Article
- Possible pharmacogenetic factors in clozapine treatment failure: a case report.Therapeutic advances in psychopharmacology · 2021Article
- Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia.Frontiers in pharmacology · 2021Article
- The association of genetic polymorphisms in CYP1A2, UGT1A4, and ABCB1 with autonomic nervous system dysfunction in schizophrenia patients treated with olanzapine.BMC psychiatry · 2020Article
- Predicting novel genomic regions linked to genetic disorders using GWAS and chromosome conformation data - a case study of schizophrenia.Scientific reports · 2019Article
- Emerging Roles of Aryl Hydrocarbon Receptors in the Altered Clearance of Drugs during Chronic Kidney Disease.Toxins · 2019Review
- The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension.Antimicrobial agents and chemotherapy · 2018Article
- Pharmacokinetic Evaluation of Clozapine in Concomitant Use of Radix Rehmanniae, Fructus Schisandrae, Radix Bupleuri, or Fructus Gardeniae in Rats.Molecules (Basel, Switzerland) · 2016Article
- Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine.European journal of drug metabolism and pharmacokinetics · 2016Article
- Potential role of UGT1A4 promoter SNPs in anastrozole pharmacogenomics.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- Metabolite Profiling of Clozapine in Patients Switching Versus Maintaining Treatment: A Retrospective Pilot Study.Journal of clinical psychopharmacologyArticle
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
introductionClozapine (CLZ) is an FDA approved second-generation antipsychotic for refractory schizophrenia, and glucuronidation is an important pathway in its metabolism. The aim of this study was to fully characterize the CLZ glucuronidation pathway and examine whether polymorphisms in active glucuronidating enzymes could contribute to variability in CLZ metabolism.
methodsCell lines overexpressing wild-type or variant uridine diphosphate-glucuronosyltransferase (UGT) enzymes were used to determine which UGTs show activity against CLZ and its major active metabolite N-desmethylclozapine (dmCLZ). Human liver microsomes (HLM) were used to compare hepatic glucuronidation activity against the UGT genotype.
resultsSeveral UGTs including 1A1 and 1A4 were active against CLZ; only UGT1A4 showed activity against dmCLZ. UGT1A1 showed a 2.1-fold (P <0.0001) higher V(max)/K(M) for formation of the CLZ-N⁺-glucuronide than UGT1A4; UGT1A4 was the only UGT for which CLZ-5-N-glucuronide kinetics could be determined. The UGT1A4(24Pro/48Val) variant showed a 5.2-, 2.0-, and 3.4-fold (P < 0.0001 for all) higher V(max)/K(M) for the formation of CLZ-5-N-glucuronide, CLZ-N⁺-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-type UGT1A4(24Pro/48Leu). There was a 37% (P< 0.05) decrease in the rate of CLZ-N⁺-glucuronide formation in HLM with the UGT1A1 (*28/*28)/UGT1A4 (*1/*1) genotype, and a 2.2- and 1.8-fold (P < 0.05 for both) increase in the formation of CLZ-5-N-glucuronide and CLZ-N⁺-glucuronide in UGT1A1 (*1/*1)/UGT1A4 (*3/*3) HLM compared with UGT1A1 (*1/*1)/UGT1A4 (*1/*1) HLM. The UGT1A1*28 allele was a significant (P = 0.045) predictor of CLZ-N⁺-glucuronide formation; the UGT1A4*3 allele was a significant (P < 0.0001) predictor of CLZ-5-N-glucuronide and dmCLZ-glucuronide formation.
conclusionThese data suggest that the UGT1A1*28 and UGT1A4*3 alleles contribute significantly to the interindividual variability in CLZ and dmCLZ metabolism.
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