In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors.
Article Details
- CitationCopy to clipboard
Filppula AM, Neuvonen PJ, Backman JT
In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors.
Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8.
- PubMed ID
- 24713129 [ View in PubMed]
- Abstract
Previous studies have shown that several protein kinase inhibitors are time-dependent inhibitors of cytochrome P450 (CYP) 3A. We screened 14 kinase inhibitors for time-dependent inhibition of CYP2C8 and CYP3A. Amodiaquine N-deethylation and midazolam 1'-hydroxylation were used as marker reactions for CYP2C8 and CYP3A activity, respectively. A screening, IC50 shift, and mechanism-based inhibition were assessed with human liver microsomes. In the screening, bosutinib isomer 1, crizotinib, dasatinib, erlotinib, gefitinib, lestaurtinib, nilotinib, pazopanib, saracatinib, sorafenib, and sunitinib exhibited an increased inhibition of CYP3A after a 30-min preincubation with NADPH, as compared with no preincubation. Axitinib and vandetanib tested negative for time-dependent inhibition of CYP3A and CYP2C8, and bosutinib was the only inhibitor causing time-dependent inhibition of CYP2C8. The inhibitory mechanism by bosutinib was consistent with weak mechanism-based inhibition, and its inactivation variables, inhibitor concentration that supports half-maximal rate of inactivation (KI) and maximal inactivation rate (kinact), were 54.8 microM and 0.018 1/min. As several of the tested inhibitors were reported to cause mechanism-based inactivation of CYP3A4 during the progress of this work, detailed experiments with these were not completed. However, lestaurtinib and saracatinib were identified as mechanism-based inhibitors of CYP3A. The KI and kinact of lestaurtinib and saracatinib were 30.7 microM and 0.040 1/min, and 12.6 microM and 0.096 1/min, respectively. Inhibition of CYP2C8 by bosutinib was predicted to have no clinical relevance, whereas therapeutic lestaurtinib and saracatinib concentrations were predicted to increase the plasma exposure to CYP3A-dependent substrates by >/=2.7-fold. The liability of kinase inhibitors to affect CYP enzymes by time-dependent inhibition may have long-lasting consequences and result in clinically relevant drug-drug interactions.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Bosutinib Cytochrome P450 2C8 Protein Humans UnknownInhibitorDetails Bosutinib Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails Crizotinib Cytochrome P450 3A Subfamily (Protein Group) Protein group Humans UnknownSubstrateInhibitorDetails Crizotinib Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails Crizotinib Cytochrome P450 3A5 Protein Humans UnknownSubstrateInhibitorDetails Erlotinib Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails Gefitinib Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails Lestaurtinib Cytochrome P450 3A4 Protein Humans NoInhibitorDetails Saracatinib Cytochrome P450 3A4 Protein Humans NoInhibitorDetails Sunitinib Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails