ArticleEuropean journal of clinical pharmacology2025
Pharmacogenetics and pharmacometabolomics predictors of clozapine and norclozapine pharmacokinetic exposure in healthy volunteers.
Article in European journal of clinical pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07262736 (Pharmacokinetics of Clozapine and Norclozapine and the Effect of Pantoprazole), which is not on this map. Not yet cited in PubMed.
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Pharmacokinetics of Clozapine and Norclozapine and the Effect of Pantoprazole
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8 authors.
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Abstract
purposeClozapine is the only effective medication for unresponsive schizophrenia. However, it has a complicated dose-concentration relationship. The present study aimed to investigate the role of some genetic polymorphisms and metabolic profiles in addressing the variability in clozapine and norclozapine concentrations.
methodsA single dose of 12.5 mg clozapine was administered to 33 healthy volunteers, from whom 270 samples were collected at 30 min, 1, 2, 3, 5, and 8 h. The concentrations of clozapine and norclozapine were determined using HPLC-UV. CYP1A2 -163 C>A, ABCB1 3435 C>T, and ABCB1 2677 G>T genetic polymorphisms were investigated using allele-specific polymerase chain reaction and restriction fragment length polymorphism, and the metabolic profiles were identified using proton nuclear magnetic resonance (
resultsClozapine concentrations and area under the curve (AUC) were higher, and the clearance was 38.3% (95% confidence intervals (95% CI), 4.5-72.2%) lower in the CYP1A2 -163 AA genotype, while clozapine initial concentrations were lower in the ABCB1 2677 GG genotype. In a multiple regression analysis, glucose (p-value, 0.009) was significantly associated with the norclozapine to clozapine AUC (N:C) ratio.
conclusionsVariabilities in clozapine pharmacokinetics were accounted for using genetic polymorphisms and metabolic profiles. Clozapine concentrations in CYP1A2 -163 C>A polymorphism should be cautiously interpreted considering the smoking status. Altered glucose levels, besides being an adverse effect of clozapine, may also be indirectly associated with variability in CYP1A2 activity as indicated by the N:C ratio to be confirmed in larger and controlled trials.
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