Nilotinib Alters the Efflux Transporter-Mediated Pharmacokinetics of Afatinib in Mice

Ronilda R. D'Cunha, Daryl J Murry, Guohua An

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3434-3442
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume108
Issue number10
DOIs
StatePublished - Oct 1 2019

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Protein-Tyrosine Kinases
Pharmacokinetics
P-Glycoprotein
Breast Neoplasms
Area Under Curve
Proteins
Heterografts
Antineoplastic Agents
BIBW 2992
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Neoplasms
Safety
Therapeutics
Pharmaceutical Preparations

Keywords

  • P-glycoprotein
  • breast cancer resistance protein
  • combination therapy
  • efflux pumps
  • pharmacokinetics
  • tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Nilotinib Alters the Efflux Transporter-Mediated Pharmacokinetics of Afatinib in Mice. / D'Cunha, Ronilda R.; Murry, Daryl J; An, Guohua.

In: Journal of Pharmaceutical Sciences, Vol. 108, No. 10, 01.10.2019, p. 3434-3442.

Research output: Contribution to journalArticle

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abstract = "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.",
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