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Drug Metab Dispos. 2019 Sep 6. pii: dmd.119.088823. doi: 10.1124/dmd.119.088823. [Epub ahead of print]

Inter-Individual Variation in CYP3A Activity Influences Lapatinib Bioactivation.

Author information

1
Lipscomb University.
2
Lipscomb University College of Pharmacy.
3
Lipscomb University College of Pharmacy and Health Sciences.
4
University of North Carolina at Chapel Hill klarissa.jackson@unc.edu.

Abstract

Lapatinib is a dual tyrosine kinase inhibitor associated with rare but potentially severe idiosyncratic hepatotoxicity. We have previously shown that cytochromes P450 (CYP) 3A4 and CYP3A5 quantitatively contribute to lapatinib bioactivation leading to formation of a reactive, potentially toxic quinoneimine. CYP3A5 is highly polymorphic; however, the impact of CYP3A5 polymorphism on lapatinib metabolism has not been fully established. The goal of this study was to determine the effect of CYP3A5 genotype and individual variation in CYP3A activity on the metabolic activation of lapatinib using human-relevant in vitro systems. Lapatinib metabolism was examined using CYP3A5-genotyped human liver microsomes and cryopreserved human hepatocytes. CYP3A and CYP3A5-selective activities were measured in liver tissues using probe substrates midazolam and T-5 (T-1032), respectively, to evaluate the correlation between enzymatic activity and lapatinib metabolite formation. Drug metabolites were measured by HPLC - tandem mass spectrometry. Further, the relative contributions of CYP3A4 and CYP3A5 to lapatinib O-debenzylation were estimated using selective chemical inhibitors of CYP3A. The results from this study demonstrated that lapatinib O-debenzylation and quinoneimine-GSH conjugate formation were highly correlated with hepatic CYP3A activity, as measured by midazolam 1'-hydroxylation. CYP3A4 played a dominant role in lapatinib bioactivation in all liver tissues evaluated. The CYP3A5 contribution to lapatinib bioactivation varied by individual donor and was dependent on CYP3A5 genotype and activity. CYP3A5 contributed approximately 20-42% to lapatinib O-debenzylation in livers from CYP3A5 expressers. These findings indicate that individual CYP3A activity, not CYP3A5 genotype alone, is a key determinant of lapatinib bioactivation and likely influences exposure to reactive metabolites. SIGNIFICANCE STATEMENT: This is the first study to examine the effect of CYP3A5 genotype, total CYP3A activity, and CYP3A5-selective activity on lapatinib bioactivation in individual human liver tissues. The results of this investigation indicate that lapatinib bioactivation via oxidative O-debenzylation is highly correlated with total hepatic CYP3A activity, and not CYP3A5 genotype alone. These findings provide insight into the individual factors, namely CYP3A activity, that may affect individual exposure to reactive, potentially toxic metabolites of lapatinib.

KEYWORDS:

anticancer agents; bioactivation; cytochrome P450; hepatocytes; pharmacogenetics/pharmacogenomics

PMID:
31492693
DOI:
10.1124/dmd.119.088823
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