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Metabolic, genetic, and pharmacokinetic parameters for the prediction of olanzapine efficacy.
- Source :
-
European Journal of Pharmaceutical Sciences . Oct2022, Vol. 177, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
-
Abstract
- • There are individual differences in the clinical use of olanzapine. • The polymorphism of the GABA-T gene has an impact on the metabolism of 5-hydroxytryptamine. • The polymorphism of the GABA-T gene is related to the pharmacokinetics of olanzapine. • Lysophosphatidylethanolamine (0:0/18:3), lysophosphatidylethanolamine (0:0/22:5), and octadecatrienoic acid can distinguish subjects with high and low olanzapine drug oral clearance rate. • The study provides an important basis for individualized medication of olanzapine. Clinical use of the a olanzapine has significantly different individual-to-individual outcomes. Accordingly, this study aimed to develop a means of predicting response to olanzapine using a combined approach based on pharmacokinetics, pharmacometabonomics, and genetic polymorphism. The olanzapine pharmacokinetics of 19 healthy volunteers treated with orally disintegrating tablets were determined using high-performance liquid chromatography–tandem mass spectrometry. Metabolic profiling and phenotyping were performed on the blood samples that remained after pharmacokinetic analysis using ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry. Uridine diphosphate-glucuronosyltransferase (UGT), tyrosine hydroxylase (TH), γ-aminobutyric acid transaminase (GABA-T), and succinic semialdehyde dehydrogenase (SSADH) were identified as key genes. The single nucleotide polymorphism genotypes most related to drug metabolism were investigated by polymerase chain reaction and Sanger sequencing. Forty-one metabolites (p < 0.05) are increased or decreased after treatment with olanzapine. Tryptophan metabolism, norepinephrine metabolism, and γ-aminobutyric acid metabolism were identified as being related to the effects of olanzapine. Subjects carrying rs1641031 AC and CC exhibited a 59.2% increase in the mean peak concentration (C max) value and a 25.33% decrease in the mean oral clearance rate (CL/F) value, compared to that in subjects with the GABA-T rs1641031 AA genotype (p < 0.05). Moreover, polymorphism of the GABA-T gene has an impact on the metabolism of 5-hydroxytryptamine. Lysophosphatidylethanolamine (0:0/18:3), lysophosphatidylethanolamine (0:0/22:5), and octadecatrienoic acid distinguish subjects with high and low olanzapine drug oral clearance and are thus identified as biomarkers for predicting its efficacy. [Display omitted] [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09280987
- Volume :
- 177
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 158779091
- Full Text :
- https://doi.org/10.1016/j.ejps.2022.106277