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ABSTRACT: PHH baseline samples

PROVIDER: PRJEB23590 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR2203450_1.fastq.gz	Fastqsanger.gz
	ERR2203450_2.fastq.gz	Fastqsanger.gz
	ERR2203451_1.fastq.gz	Fastqsanger.gz
	ERR2203451_2.fastq.gz	Fastqsanger.gz
	ERR2203452_1.fastq.gz	Fastqsanger.gz

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Project description:Imatinib is a tyrosine kinase inhibitor (TKI) indicated for chronic myeloid leukemia (CML) and other cancers. It is metabolized by CYP2C8 and CYP3A into a major active metabolite N-desmethyl-imatinib. The purpose of the study was to determine in vitro the influence of CYP2C8 and CYP3A phenotypes, such as protein concentration and activity, and genotypes on imatinib clearance and N-desmethyl imatinib formation. Individual-donor and pooled human liver microsomes (HLM) and primary human hepatocytes (PHH) were incubated with imatinib to determine the rate of clearance of imatinib and formation of N-desmethyl-imatinib. HLMs were also investigated to determine their CYP2C8 and CYP3A activity and protein concentrations. Results were compared to evaluate the relationship between the CYP phenotypes and imatinib clearance and N-desmethyl-imatinib formation. For PHH samples, CYP2C8, CYP3A4, and CYP3A5 genotypes were also determined and imatinib metabolism was compared between the genotype groups. CYP3A5 metabolizer phenotype groups were also used to compare CYP phenotypes and imatinib metabolism in the PHH samples. The CYP targeted proteomics concentration measurements for the HLMs were undertaken on a nanoLC-QTRAP 5500 system (SCIEX mass spectrometer, Framingham, MA, USA) and the PHH measurements were determined on a microLC-Triple quadrupole 7500 system (also SCIEX mass spectrometer). Unlike the HLMs, membrane protein was extracted from the PHH samples before being trypsin digested. The data showed that, in HLM donors, CYP3A activity was the most significant predictor of imatinib clearance while CYP2C8 activity was the most significant predictor of N-desmethyl-imatinib formation. Additionally, in PHH, imatinib clearance was more significantly correlated with CYP2C8 phenotypes than CYP3A phenotypes. There was a significant difference in imatinib clearance between CYP2C8*1/*1 individuals and CYP2C8*3 carriers in PHH donors. Overall, the results support previous work that CYP2C8 plays a key role in imatinib metabolism and could provide insight into interindividual variability seen in patients taking the medication.

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