Dataset Information

Impact of Variation in CYP3A and CYP2C8 on Tucatinib Metabolic Clearance in Human Liver Microsomes

ABSTRACT: Tucatinib is a tyrosine kinase inhibitor (TKI) indicated for HER2 positive breast cancer. It is metabolized primarily by cytochrome P450 (CYP) 2C8 and CYP3A. Given the interindividual variability in the pharmacokinetics of some TKIs, this study explored how variability in CYP2C8 and CYP3A activities and concentrations can influence variability in overall tucatinib metabolic clearance. Tucatinib depletion, CYP activities, and CYP concentrations were measured in human liver microsomes from 21 donors (males n = 11, females n = 10). Specifically, CYP2C8, CYP3A4, and CYP3A5 protein concentrations were measured using quantitative targeted absolute proteomics (QTAP), and the raw data for this, including peak area data, are deposited here. Tucatinib clearance was significantly correlated with both CYP2C8 and CYP3A enzyme activities and protein concentrations in the donor cohort. A multiple linear regression model was developed to determine the most significant parameters influencing tucatinib clearance. The model including only CYP2C8 and CYP3A activities provided the best fit, indicating a strong predictive ability. Overall, CYP3A activity was the most significant predictor of tucatinib clearance in the human liver microsomal samples tested.

INSTRUMENT(S): Q TRAP

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: John Fallon

LAB HEAD: Klarissa Jackson

PROVIDER: PXD057282 | Pride | 2025-04-17

REPOSITORIES: Pride

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Source:

			Action	DRS
	HLM_QC_Digests_6th_April_2023__UGTs_CYP450s.qsession	Other
	HLMs_6th_April_2023__UGTs_CYP450s.wiff	Wiff
	HLMs_6th_April_2023__UGTs_CYP450s.wiff.scan	Wiff
	HLMs_Digests_6th_April_2023__UGTs_CYP450s.qsession	Other
	HLMs_QC_6th_April_2023.wiff	Wiff

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Impact of Variation in CYP3A and CYP2C8 on Tucatinib Metabolic Clearance in Human Liver Microsomes

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