TY - JOUR
T1 - Nilotinib Alters the Efflux Transporter-Mediated Pharmacokinetics of Afatinib in Mice
AU - D'Cunha, Ronilda R.
AU - Murry, Daryl J.
AU - An, Guohua
N1 - Publisher Copyright:
© 2019 American Pharmacists Association®
PY - 2019/10
Y1 - 2019/10
N2 - Small-molecule tyrosine kinase inhibitors (TKIs) are novel anticancer agents with enhanced selectivity and superior safety profiles than conventional chemotherapeutics. A major shortcoming in TKI therapy is the development of acquired resistance. An important resistance mechanism is reduced intracellular drug accumulation due to an overexpression of efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in cancer cells. TKIs have dual roles as substrates and inhibitors of Pgp and BCRP; thus, combination TKI therapy could potentially reverse efflux transporter-mediated TKI resistance. In the present study, the effect of 14 TKIs on Pgp-, Bcrp1-, and BCRP-mediated afatinib efflux was investigated in vitro. Nilotinib was a potent inhibitor of Pgp, Bcrp1, and BCRP, with EC50 values of 2.22, 2.47, and 0.692 μM, respectively. Consequently, the pharmacokinetics of afatinib with and without the coadministration of nilotinib was determined in mice plasma and various tissues. Nilotinib increased afatinib AUC by 188% in plasma, and this altered tissue AUC by −38.8% to +221%. Nilotinib also decreased the clearance of afatinib by 65.3%, from 609 to 211 mL/h. Further studies are warranted to assess nilotinib's chemosensitizing effect in tumor xenograft models.
AB - Small-molecule tyrosine kinase inhibitors (TKIs) are novel anticancer agents with enhanced selectivity and superior safety profiles than conventional chemotherapeutics. A major shortcoming in TKI therapy is the development of acquired resistance. An important resistance mechanism is reduced intracellular drug accumulation due to an overexpression of efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in cancer cells. TKIs have dual roles as substrates and inhibitors of Pgp and BCRP; thus, combination TKI therapy could potentially reverse efflux transporter-mediated TKI resistance. In the present study, the effect of 14 TKIs on Pgp-, Bcrp1-, and BCRP-mediated afatinib efflux was investigated in vitro. Nilotinib was a potent inhibitor of Pgp, Bcrp1, and BCRP, with EC50 values of 2.22, 2.47, and 0.692 μM, respectively. Consequently, the pharmacokinetics of afatinib with and without the coadministration of nilotinib was determined in mice plasma and various tissues. Nilotinib increased afatinib AUC by 188% in plasma, and this altered tissue AUC by −38.8% to +221%. Nilotinib also decreased the clearance of afatinib by 65.3%, from 609 to 211 mL/h. Further studies are warranted to assess nilotinib's chemosensitizing effect in tumor xenograft models.
KW - P-glycoprotein
KW - breast cancer resistance protein
KW - combination therapy
KW - efflux pumps
KW - pharmacokinetics
KW - tyrosine kinase inhibitors
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U2 - 10.1016/j.xphs.2019.05.028
DO - 10.1016/j.xphs.2019.05.028
M3 - Article
C2 - 31163185
AN - SCOPUS:85067898517
SN - 0022-3549
VL - 108
SP - 3434
EP - 3442
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 10
ER -