title: Influence of the multidrug transporter P-glycoprotein on the intracellular pharmacokinetics of vandetanib.
abstract: Efflux transporters play an important role in the resistance of tumor cells against anticancer agents. Interaction between these transporters, including P-glycoprotein (P-gp), and drugs might influence their pharmacological properties and toxicities. The aim of this study was to investigate whether vandetanib (Caprelsa(®)), a small tyrosine kinase inhibitor, could interact with the multidrug transporter P-gp. Interaction of vandetanib with the P-gp was investigated using the parental cell line (IGROV1) and the P-gp doxorubicin-resistant (IGROV1-DXR) cell line, derived from the parental drug-sensitive IGROV1 cells. Cytotoxicity tests were assessed in both cell lines to examine the impact of P-gp on the cell survival after a vandetanib treatment. The effects of P-gp on vandetanib intracellular pharmacokinetics were investigated. To this aim, we developed a quantitative liquid chromatography tandem mass spectrometry to quantify vandetanib in cell medium. Results showed that overexpression of P-gp confers resistance to vandetanib in the IGROV1-DXR cell line. Using a LC-MS/MS assay validated in cell medium, cellular pharmacokinetic studies revealed that in cells overexpressing the P-gp intracellular concentrations of vandetanib were decreased compared to parental cell line. For the first time, vandetanib is described as a substrate of P-gp. In tumor cells, P-gp could be responsible for cellular resistance to vandetanib. It may be relevant to the clinical efficacy of vandetanib. Moreover, interaction of vandetanib with P-gp could modify the pharmacodynamics of other conventional chemotherapeutics, substrates of P-gp. It could impact on the overall response to anticancer therapy.
authors: Faculty of Pharmacy, EA4123, Barrières physiologiques et réponses thérapeutiques, Univ Paris-Sud 11, Châtenay-Malabry, France, cecile.jovelet@u-psud.fr.
authors: C
authors: C
authors: Jovelet
authors: A
authors: A
authors: Deroussent
authors: S
authors: S
authors: Broutin
authors: A
authors: A
authors: Paci
authors: R
authors: R
authors: Farinotti
authors: J M
authors: JM
authors: Bidart
authors: S
authors: S
authors: Gil
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D010880:Piperidines / Q000493:pharmacokinetics* / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000633:toxicity; D053719:Tandem Mass Spectrometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D004317:Doxorubicin; C452423:vandetanib