Involvement of
Pazopanib and Sunitinib Aldehyde Reactive
Metabolites in Toxicity and Drug–Drug Interactions in Vitro and in Patient Samples
Posted on 2019-09-26 - 19:16
Tyrosine kinase inhibitors
(TKI) are targeted anticancer drugs
that have been successfully developed over the past 2 decades. To
date, many of them (around 70%) require warnings for liver injury
and five of them, including pazopanib and sunitinib, have Black Box
Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first
cause of drug failures in clinical trials, BBW labels, and market
withdrawals, the underlying mechanisms remain unclear. However, the
recent discovery of new reactive metabolites (RM) with aldehyde structures
during pazopanib and sunitinib metabolism offers new perspectives
for investigating their involvement in the toxicity of these two TKI.
These hard electrophiles have a high reactivity potential toward proteins
and are thought to be responsible for cytochrome P450 inactivation,
drug–drug interactions (DDI), and liver toxicity. We report
here, for the first time, the presence of these aldehyde RM in human
plasma samples obtained during drug monitoring. Docking experiments
in the CYP3A4 active site were performed and showed that pazopanib
and sunitinib fitting in the catalytic site are in accordance with
their regioselective oxidation to aldehydes. They also suggested that
aldehyde RM may react with lysine and arginine residues. Based on
these results, we studied the reactivity of the aldehyde RM toward
lysine and arginine residues as potential targets on the protein framework
to better understand how these RM could be involved in liver toxicity
and drug–drug interactions. Adduct formation with different
hepatic and plasma proteins was investigated by LC-MS/MS, and adducts
between pazopanib or sunitinib aldehyde derivatives and lysine residues
on both CYP3A4 and plasma proteins were indeed shown for the first
time.
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Paludetto, Marie-Noëlle; Stigliani, Jean-Luc; Robert, Anne; Bernardes-Génisson, Vania; Chatelut, Etienne; Puisset, Florent; et al. (2019). Involvement of
Pazopanib and Sunitinib Aldehyde Reactive
Metabolites in Toxicity and Drug–Drug Interactions in Vitro and in Patient Samples. ACS Publications. Collection. https://doi.org/10.1021/acs.chemrestox.9b00205
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AUTHORS (7)
MP
Marie-Noëlle Paludetto
JS
Jean-Luc Stigliani
AR
Anne Robert
VB
Vania Bernardes-Génisson
EC
Etienne Chatelut
FP
Florent Puisset
CA
Cécile Arellano