Title : Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates.

Pub. Date : 2012 Apr

PMID : 22014153






14 Functional Relationships(s)
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1 Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
2 Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
3 BACKGROUND AND PURPOSE: Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
4 BACKGROUND AND PURPOSE: Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
5 BACKGROUND AND PURPOSE: Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
6 KEY RESULTS: Inhibition of CYP3A4 activity by imatinib was pre-incubation time-, concentration- and NADPH-dependent, and the time-dependent inactivation variables K(I) and k(inact) were 14.3 microM and 0.072 in(-1) respectively. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
7 The time-dependent inhibition effect of imatinib was predicted to cause up to 90% inhibition of hepatic CYP3A4 activity with clinically relevant imatinib concentrations, whereas the direct inhibition was predicted to be negligible in vivo. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
8 The time-dependent inhibition effect of imatinib was predicted to cause up to 90% inhibition of hepatic CYP3A4 activity with clinically relevant imatinib concentrations, whereas the direct inhibition was predicted to be negligible in vivo. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
9 CONCLUSIONS AND IMPLICATIONS: Imatinib is a potent mechanism-based inhibitor of CYP3A4 in vitro and this finding explains the imatinib-simvastatin interaction and suggests that imatinib could markedly increase plasma concentrations of other CYP3A4 substrates. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
10 CONCLUSIONS AND IMPLICATIONS: Imatinib is a potent mechanism-based inhibitor of CYP3A4 in vitro and this finding explains the imatinib-simvastatin interaction and suggests that imatinib could markedly increase plasma concentrations of other CYP3A4 substrates. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
11 CONCLUSIONS AND IMPLICATIONS: Imatinib is a potent mechanism-based inhibitor of CYP3A4 in vitro and this finding explains the imatinib-simvastatin interaction and suggests that imatinib could markedly increase plasma concentrations of other CYP3A4 substrates. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
12 Our results also suggest a possibility of autoinhibition of CYP3A4-mediated imatinib metabolism leading to a less significant role for CYP3A4 in imatinib biotransformation in vivo than previously proposed. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
13 Our results also suggest a possibility of autoinhibition of CYP3A4-mediated imatinib metabolism leading to a less significant role for CYP3A4 in imatinib biotransformation in vivo than previously proposed. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens
14 Our results also suggest a possibility of autoinhibition of CYP3A4-mediated imatinib metabolism leading to a less significant role for CYP3A4 in imatinib biotransformation in vivo than previously proposed. Imatinib Mesylate cytochrome P450 family 3 subfamily A member 4 Homo sapiens