Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro.
Article Details
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Weiss J, Theile D, Dvorak Z, Haefeli WE
Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro.
Pharmaceutics. 2014 Dec 16;6(4):632-50. doi: 10.3390/pharmaceutics6040632.
- PubMed ID
- 25521244 [ View in PubMed]
- Abstract
Dovitinib (TKI-258) is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1) inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2) by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs) by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR) activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 +/- 4.5 muM). Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3), and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug-drug interactions.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Dovitinib Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownSuppressorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dovitinib Cytochrome P450 1A1 Protein Humans UnknownInducerDetails Dovitinib Cytochrome P450 1A2 Protein Humans UnknownInducerDetails Dovitinib Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails Dovitinib Cytochrome P450 3A4 Protein Humans UnknownInhibitorDetails Dovitinib UDP-glucuronosyltransferase 1-3 Protein Humans UnknownInhibitorDetails Dovitinib UDP-glucuronosyltransferase 2B7 Protein Humans UnknownInhibitorDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Dovitinib ATP-binding cassette sub-family G member 2 Protein Humans UnknownInhibitorInducerDetails Dovitinib Canalicular multispecific organic anion transporter 2 Protein Humans UnknownNot Available Details Dovitinib P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Dovitinib Solute carrier organic anion transporter family member 1B1 Protein Humans UnknownInhibitorDetails Dovitinib Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownInhibitorDetails Dovitinib Solute carrier organic anion transporter family member 2B1 Protein Humans UnknownInhibitorDetails