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In vitro assessment of mechanism-based CYP2C8 and CYP3A4 inhibition by six protein kinase inhibitors

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Title: In vitro assessment of mechanism-based CYP2C8 and CYP3A4 inhibition by six protein kinase inhibitors
Author(s): Mustonen, Tiffany
Contributor: University of Helsinki, Faculty of Medicine
Discipline: Clinical Pharmacology and Pharmacotherapy
Language: English
Acceptance year: 2016
Several protein kinase inhibitors are known to be mechanism-based inhibitors of cytochrome P450 (CYP) enzymes, especially CYP3A4. Mechanism-based inhibition of CYP enzymes by a drug may have long lasting and serious consequences due to the irreversible nature of the inhibition. The CYP enzyme must be resynthesized before regaining functionality, affecting the concentrations of other drugs metabolized by the same CYP enzymes and potentially leading to drug-drug interactions. Six protein kinase inhibitors were tested for mechanism-based inhibition of CYP2C8 and CYP3A4 using human liver microsomes; masitinib, midostaurin, nintedanib, quizartinib, trametinib and vatalanib. Amodiaquine was used as the substrate for CYP2C8, while midazolam was the CYP3A4 substrate. None of the inhibitors tested displayed time-dependent inhibition of CYP2C8. Midostaurin and nintedanib exhibited time-dependent inhibition of CYP3A4 while masitinib, quizartinib, trametinib and vatalanib did not. Both midostaurin and nintedanib had an inhibitor concentration causing a 50% inhibition (IC50) shift of >1.5-fold with increased inhibition of CYP3A4 after preincubation with NADPH for 30 minutes when compared to no preincubation. The mechanism-based inactivation constants kinact (the maximal inactivation rate) and KI (the inhibitor concentration that supports half-maximal rate of inactivation) were determined for midostaurin and nintedanib. The kinact values were 0.053 1/min for midostaurin and 0.024 1/min for nintedanib, while the KI values were 2.65 µM for midostaurin and 16.5 µM for nintedanib. Predictions using a mechanistic static model suggested that nintedanib is unlikely to cause CYP3A4 mediated drug-drug interactions, while midostaurin was predicted to increase the exposure of CYP3A4 substrates by several times. Reversible inhibition by trametinib is unlikely to cause drug-drug interactions involving either CYP2C8 or CYP3A4 substrates. On the other hand, masitinib and vatalanib were predicted to increase the exposure of CYP2C8 and CYP3A4 substrates several fold. In conclusion, two protein kinase inhibiters were identified as mechanism-based inhibitors of CYP3A. Mechanism-based inhibition of CYP enzymes by protein kinase inhibitors has the potential to cause severe long lasting consequences and careful testing should be conducted to determine the actual clinical drug-drug interaction risk.
Keyword(s): CYP2C8 CYP3A4 Drug-drug interaction Mechanism-based inhibition Protein kinase inhibitors Time-dependent inhibition

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