Abstract
Tyrosine kinase inhibitors (TKIs) are anticancer drugs that may be co-administered with other drugs. The aims of this study are to investigate the inhibitory effects of TKIs on UDP-glucuronosyltransferase (UGT) activities, and to quantitatively evaluate their potential to cause drug-drug interactions (DDIs). Inhibition kinetic profiles of a panel of UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17) by four TKIs (axitinib, imatinib, lapatinib and vandetanib) were characterized by using hepatic microsomes and recombinant proteins. Lapatinib exhibited potent competitive inhibition against UGT1A1 activity with a Ki of 0.5 μM. Imatinib was found to exhibit broad inhibition on several UGTs, particularly potent competitive inhibition against UGT2B17 with a Ki of 0.4 μM. The TKIs also exerted intermediate inhibition against several UGTs (i.e., UGT1A7 by lapatinib; UGT1A1 by imatinib; UGT1A4, 1A7 and 1A9 by axitinib; and UGT1A9 by vandetanib). Results from modeling for the quantitative prediction of DDI risk indicated that the coadministration of lapatinib or imatinib at clinical doses could result in a significant increase in AUC of drugs primarily cleared by UGT1A1 or 2B17. Lapatinib and imatinib may cause clinically significant DDIs when co-administered UGT1A1 or 2B17 substrates.
Highlights
A clinical study showed that co-administration of lapatinib with irinotecan led to a ~40% increase in the AUC of SN-3816, suggesting the possible inhibition of UGT1A1 activity by lapatinib
The results showed that at 100 μ M concentration, Tyrosine kinase inhibitors (TKIs) inhibited the activity of UGT isoforms to varying extent (Table 1)
We selected four commonly used TKIs, including two 4-anilinoquinazolines, one pyrimidine and one indazol to investigate whether these TKIs could inhibit a panel of UGTs activities
Summary
Previous in vitro and in vivo studies indicate that TKIs may alter the hepatic elimination of co-administered drugs by inhibiting their metabolism. A clinical study showed that co-administration of lapatinib with irinotecan led to a ~40% increase in the AUC of SN-38 (an active metabolite of irinotecan and a UGT1A1 substrate)[16], suggesting the possible inhibition of UGT1A1 activity by lapatinib. Whether these TKIs affect activities of others UGT isoforms and whether other TKIs affect UGTs remain unknown. The inhibition kinetics of each compound was further characterized, and the risks for clinically significant drug-drug interactions were estimated
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